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Bacteriologic relapse during ampicillin treatment of Hemophilus influenzae meningitis
BRIEF CLINICAL AND LABORATORY OBSERVATIONS
Bacteriologic relapse during ampicillin treatment of Hemophilus influenzae meningitis A. J. Gold, M . D . , Ellin L i e b e r m a n , M . D . , a n d H a r r y T . W r i g h t , Jr., M . D . LOS ANGELES~
CALIF.
A v t P I c I L L I N is a safe a n d effective agent in the t r e a t m e n t of Hemophilus influenzae meningitis. 1-~ N o strains of Hemophilus influenzae which are resistant to ampicillin have been isolated in the extensive studies by W e h r l e a n d associates. 4, 5 H o w ever, 3 instances of bacteriologic relapse in HemophiIus influenzae meningitis t r e a t e d with ampicillin have been r e p o r t e d 2 -s I n one case of meningitis t r e a t e d by the oral route, 6 relapse was a t t r i b u t e d to i n a d e q u a t e conc e n t r a t i o n of ampicillin in the cerebrospinal fluid. I n a n o t h e r patient, s relapse was also a t t r i b u t e d to i n a d e q u a t e c o n c e n t r a t i o n of the antibiotic in the cerebrospinal fluid. I n a third r e p o r t 7 relapse was a t t r i b u t e d to sequestration of organisms at a site (cellulitis or ethmoiditis) inaccessible or only p a r t i a l l y accessible to the d r u g ; the second l u m b a r p u n c t u r e in this last p a t i e n t revealed n e i t h e r cells nor organisms. T h e following is the case r e p o r t of a n a d d i tional infant w h o h a d a bacteriologic re-
From the Childrens Hospital o[ Los Angeles. Supported in part by Fund No. 78001 (Bacterial Meningitis Research) o[ the Childrens Hospital o[ Los Angeles. Address: Childrens Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, Call[. 90027.
lapse while being t r e a t e d for Hemophilus influenzae meningitis with the usually reco m m e n d e d dosage of ampicillin. CASE REPORT
A 7-month-old Negro girl was admitted to Childrens Hospital of Los Angeles with a 24 hour history of fever to 41 ~ C. and progressive lethargy. She had been examined by her family physician 12 hours prior to admission, at which time procaine penicillin was administered intramuscularly and oral oxytetracycline was prescribed. Her symptoms persisted and the infant was brought to the emergency room of the hospital. She was lethargic but responded to stimulation. The patient had no known immunologic or anatomic defect and no known underlying disease. Her rectal temperature was 40 ~ C. and pulse 120. The anterior fontanelle was flat and soft; funduscopic examination showed no abnormality. The left tympanic membrane was slightly inflamed but not bulging; the right tympanic membrane appeared normal. The tonsils and posterior pharynx were moderately inflamed. She had moderate nuchaI rigidity and positive Kernig's and Brudzinski's signs; however, deep tendon reflexes were normal and cranial nerves were intact by examination. A lumbar puncture yielded cerebrospinal fluid (CSF) containing 370 white blood cells pet" cubic millimeter, of which 30 per cent were neutrophils and 70 per cent were mononuclear cells. The CSF sugar was 23 mg. per 100 mI. (a blood sugar obtained simultaneously was 74 mg. per cent), and the CSF protein was 71 mg. per 100 ml. No organisms were detected in gram-stained CSF sediment, but both CSF and blood cultures yielded Hemophilus influenzae type b. Peripheral leukocyte count was 19,500 with 56 per cent segmented neutrophils, 7 per cent band forms, and 37 per cent lymphocytes. Serum electrolytes and blood urea nitrogen were normal. The patient initially received a single dose of ampicillin (50 mg. per kilogram) by rapid intravenous infusion and subsequently received ampicillin (150 rag. per kilogram per day) in divided doses, mixed in 10 c.c. isotonic saline and administered by a fast intravenous drip
7 8 0 Brief clinical and laboratory observations
every 4 hours. The patient improved gradually, becoming more alert and less irritable. Nuchal rigidity disappeared by the fourth hospital day; both tympanic membranes and pharynx were normal at that time. By the fifth day of therapy she was afebrile. Her condition was stable until the eighth hospital day when fever (39 ~ C.) recurred, associated with mild lethargy and emesis. The anterior fontanelle was full, but signs of meningeal irritation and other abnormal physical findings were absent. A second lumbar puncture revealed 2,700 white blood cells per cubic millimeter of CSF with 54 per cent neutrophils and 46 per cent lymphocytes; the CSF sugar was 63 mg. per 100 ml., and protein was 69 mg. per 100 ml. Gram-stained CSF sediment revealed no organisms, but CSF culture yielded Hemophilus influenzae type b sensitive to ampicillin and ehloramphenicol by the disc method. Ampicillin was discontinued and the patient was treated with intravenous ehloramphenicol (100 mg. per kilogram per day) in divided doses every 6 hours for 5 days. Radiographic examinations of the chest as well as the paranasal and mastoid sinuses on the ninth hospital day showed no abnormality. The remainder of the hospital course was uncomplicated. The patient became afebrile on the tenth hospital day. On the fourteenth hospital day a repeat lumbar puncture revealed 77 white blood cells per cubic millimeter of CSF of which 98 per cent were lymphocytes; the CSF protein was 26 rag. per 100 ml.; the CSF sugar was 45 mg. per 100 ml. and a blood sugar obtained simultaneously was 95 mg. per 100 ml. Gram stain and culture of the CSF were negative. Chloramphenicol was discontinued on the fourteenth day and the patient was observed for an additional 48 hours. She remained asymptomatic and was discharged on the sixteenth day. Followup examination findings since discharge have been within normal limits; she has remained entirely asymptomatic. DISCUSSION
Ampicillin was administered intravenously to this infant using an initial dose of 50 rag. per kilogram and 150 mg. per kilogram per day thereafter. This regimen has been considered effective by Barrett and associates ~ and Mathies and associates? The ampicillin was diluted in isotonic saline just prior to infusion and given over a 10 to 15
The ]oufnal of Pediatrics May 1969
minute period every 4 hours, thus minimizing the inactivation of the drug. Barrett and associates 2 have found that the minimal inhibitory concentration of ampicillin against various strains of Hemophilus influenzae may v a r y from 0.025 t o 0.78 /~g per milliliter in the CSF. The minimal bactericidal concentration may be more variable. Unfortunately, the organism isoIated from the present patient was not submitted to tube dilution studies using ampicillin. T h r u p p and associates 9 have shown t h a t the ratio of ampicillin in the cerebrospinal fluid, as compared with blood levels, in patients with Hemophilus influenzae meningitis drops markedly after the third day of therapy. This decrease is most likely related to the decrease i n meningeal permeability after treatment and correlates well with the decrease in both cells' and protein in 'the cerebrospinal fluid. Taber and associates 1~ have also shown that ampicillin concentrations in the cerebrospinal fluid are highest during the first 3 days of therapy and decline markedly thereafter. Although roentgenograms of the chest and sinuses failed to reveal a secon'dary source of infection, the possibili~ty of focal sequestration of the organism exists. Relapse in this patient occurred during intravenous therapy rather than after completion of therapy; however; this would be more compatible with an inadequate CSF level of ampicillin. It should be pointed out that bacteriologic relapse in the treatment of Hemophilus in 2 fluenzae meningitis has occurred with other regimens of therapy (including chlora;mphenicol) and might have been expected to occur with ampicillin therapy 24, 5, 11 The present case suggests that optimal ampicillin therapy for certain patients with Hemophilus influenzae, meningitis may be greater than 150 mg. per kilogram per day and supports the suggestion of .Cherry and Sheenan 6 that an increase in ampicillin dosage after evidence of clinical improvement might be appropriate. The authors are grateful' for the 'he!pffll suggestions of Drs. John M. Leedom and Paul F. Wehrle.
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
Bacteriologic relapse during ampicillin treatment of Hemophilus influenzae meningitis A. J. Gold, M . D . , Ellin L i e b e r m a n , M . D . , a n d H a r r y T . W r i g h t , Jr., M . D . LOS ANGELES~
CALIF.
A v t P I c I L L I N is a safe a n d effective agent in the t r e a t m e n t of Hemophilus influenzae meningitis. 1-~ N o strains of Hemophilus influenzae which are resistant to ampicillin have been isolated in the extensive studies by W e h r l e a n d associates. 4, 5 H o w ever, 3 instances of bacteriologic relapse in HemophiIus influenzae meningitis t r e a t e d with ampicillin have been r e p o r t e d 2 -s I n one case of meningitis t r e a t e d by the oral route, 6 relapse was a t t r i b u t e d to i n a d e q u a t e conc e n t r a t i o n of ampicillin in the cerebrospinal fluid. I n a n o t h e r patient, s relapse was also a t t r i b u t e d to i n a d e q u a t e c o n c e n t r a t i o n of the antibiotic in the cerebrospinal fluid. I n a third r e p o r t 7 relapse was a t t r i b u t e d to sequestration of organisms at a site (cellulitis or ethmoiditis) inaccessible or only p a r t i a l l y accessible to the d r u g ; the second l u m b a r p u n c t u r e in this last p a t i e n t revealed n e i t h e r cells nor organisms. T h e following is the case r e p o r t of a n a d d i tional infant w h o h a d a bacteriologic re-
From the Childrens Hospital o[ Los Angeles. Supported in part by Fund No. 78001 (Bacterial Meningitis Research) o[ the Childrens Hospital o[ Los Angeles. Address: Childrens Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, Call[. 90027.
lapse while being t r e a t e d for Hemophilus influenzae meningitis with the usually reco m m e n d e d dosage of ampicillin. CASE REPORT
A 7-month-old Negro girl was admitted to Childrens Hospital of Los Angeles with a 24 hour history of fever to 41 ~ C. and progressive lethargy. She had been examined by her family physician 12 hours prior to admission, at which time procaine penicillin was administered intramuscularly and oral oxytetracycline was prescribed. Her symptoms persisted and the infant was brought to the emergency room of the hospital. She was lethargic but responded to stimulation. The patient had no known immunologic or anatomic defect and no known underlying disease. Her rectal temperature was 40 ~ C. and pulse 120. The anterior fontanelle was flat and soft; funduscopic examination showed no abnormality. The left tympanic membrane was slightly inflamed but not bulging; the right tympanic membrane appeared normal. The tonsils and posterior pharynx were moderately inflamed. She had moderate nuchaI rigidity and positive Kernig's and Brudzinski's signs; however, deep tendon reflexes were normal and cranial nerves were intact by examination. A lumbar puncture yielded cerebrospinal fluid (CSF) containing 370 white blood cells pet" cubic millimeter, of which 30 per cent were neutrophils and 70 per cent were mononuclear cells. The CSF sugar was 23 mg. per 100 mI. (a blood sugar obtained simultaneously was 74 mg. per cent), and the CSF protein was 71 mg. per 100 ml. No organisms were detected in gram-stained CSF sediment, but both CSF and blood cultures yielded Hemophilus influenzae type b. Peripheral leukocyte count was 19,500 with 56 per cent segmented neutrophils, 7 per cent band forms, and 37 per cent lymphocytes. Serum electrolytes and blood urea nitrogen were normal. The patient initially received a single dose of ampicillin (50 mg. per kilogram) by rapid intravenous infusion and subsequently received ampicillin (150 rag. per kilogram per day) in divided doses, mixed in 10 c.c. isotonic saline and administered by a fast intravenous drip
7 8 0 Brief clinical and laboratory observations
every 4 hours. The patient improved gradually, becoming more alert and less irritable. Nuchal rigidity disappeared by the fourth hospital day; both tympanic membranes and pharynx were normal at that time. By the fifth day of therapy she was afebrile. Her condition was stable until the eighth hospital day when fever (39 ~ C.) recurred, associated with mild lethargy and emesis. The anterior fontanelle was full, but signs of meningeal irritation and other abnormal physical findings were absent. A second lumbar puncture revealed 2,700 white blood cells per cubic millimeter of CSF with 54 per cent neutrophils and 46 per cent lymphocytes; the CSF sugar was 63 mg. per 100 ml., and protein was 69 mg. per 100 ml. Gram-stained CSF sediment revealed no organisms, but CSF culture yielded Hemophilus influenzae type b sensitive to ampicillin and ehloramphenicol by the disc method. Ampicillin was discontinued and the patient was treated with intravenous ehloramphenicol (100 mg. per kilogram per day) in divided doses every 6 hours for 5 days. Radiographic examinations of the chest as well as the paranasal and mastoid sinuses on the ninth hospital day showed no abnormality. The remainder of the hospital course was uncomplicated. The patient became afebrile on the tenth hospital day. On the fourteenth hospital day a repeat lumbar puncture revealed 77 white blood cells per cubic millimeter of CSF of which 98 per cent were lymphocytes; the CSF protein was 26 rag. per 100 ml.; the CSF sugar was 45 mg. per 100 ml. and a blood sugar obtained simultaneously was 95 mg. per 100 ml. Gram stain and culture of the CSF were negative. Chloramphenicol was discontinued on the fourteenth day and the patient was observed for an additional 48 hours. She remained asymptomatic and was discharged on the sixteenth day. Followup examination findings since discharge have been within normal limits; she has remained entirely asymptomatic. DISCUSSION
Ampicillin was administered intravenously to this infant using an initial dose of 50 rag. per kilogram and 150 mg. per kilogram per day thereafter. This regimen has been considered effective by Barrett and associates ~ and Mathies and associates? The ampicillin was diluted in isotonic saline just prior to infusion and given over a 10 to 15
The ]oufnal of Pediatrics May 1969
minute period every 4 hours, thus minimizing the inactivation of the drug. Barrett and associates 2 have found that the minimal inhibitory concentration of ampicillin against various strains of Hemophilus influenzae may v a r y from 0.025 t o 0.78 /~g per milliliter in the CSF. The minimal bactericidal concentration may be more variable. Unfortunately, the organism isoIated from the present patient was not submitted to tube dilution studies using ampicillin. T h r u p p and associates 9 have shown t h a t the ratio of ampicillin in the cerebrospinal fluid, as compared with blood levels, in patients with Hemophilus influenzae meningitis drops markedly after the third day of therapy. This decrease is most likely related to the decrease i n meningeal permeability after treatment and correlates well with the decrease in both cells' and protein in 'the cerebrospinal fluid. Taber and associates 1~ have also shown that ampicillin concentrations in the cerebrospinal fluid are highest during the first 3 days of therapy and decline markedly thereafter. Although roentgenograms of the chest and sinuses failed to reveal a secon'dary source of infection, the possibili~ty of focal sequestration of the organism exists. Relapse in this patient occurred during intravenous therapy rather than after completion of therapy; however; this would be more compatible with an inadequate CSF level of ampicillin. It should be pointed out that bacteriologic relapse in the treatment of Hemophilus in 2 fluenzae meningitis has occurred with other regimens of therapy (including chlora;mphenicol) and might have been expected to occur with ampicillin therapy 24, 5, 11 The present case suggests that optimal ampicillin therapy for certain patients with Hemophilus influenzae, meningitis may be greater than 150 mg. per kilogram per day and supports the suggestion of .Cherry and Sheenan 6 that an increase in ampicillin dosage after evidence of clinical improvement might be appropriate. The authors are grateful' for the 'he!pffll suggestions of Drs. John M. Leedom and Paul F. Wehrle.
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