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A prospective randomized comparison of cefotaxime vs ampicillin and chloramphenicol for bacterial meningitis in children
PEDIATRIC PHARMACOLOGY A N D THERAPEUTICS
A prospective randomized comparison of cefotaxime vs ampicillin and chloramphenicol for bacterial meningitis in children Fifty children with bacterial meningitis were prospectively randomized to receive ceJotaxime (50 mg/kg/dose every 6 hours) or ampieillin and ehloramphenicol in standard doses. Twenty-three patients received cefotaxime and 27 received standard therapy. Bacterial isolates included- Haemophilus influenzae (29), Streptococcus pneumoniae (eight), Neisseria meningitidis (eight), group B streptococci (three), and Salmonella enteritidis (two). Ten (34 %) o f the H. influenzae isolates were resistant to ampicillin, nine on the basis o f ~-laetamase production. All strains were susceptible to cefotaxime. Clinical cure rates for the cefotaxime (100%) and standard therapy (96%) groups Were similar," survival without detectable sequelae was Similar, at 78% and 77%, respectively. The duration o f therapy, 11.1 +_ 2.4 days (range 10 to 21 days) vs 11.9 +_ 3.9 days (range 10 to 21 days), and days to defervescence, 4.7 +_ 2:6 days (range 1 to 14 days) vs 5.6 + 2.9 days (range 2 to 17 days), were similar in the cefotaxime and standard therapy groups, respectively. No adverse drug reactions or side effects were noted in either group. Cefotaxime was found to be as safe and effective as standard therapy for the treatment o f bacterial meningitis in children. (J PEt)I.~TR 107:i29, 1985)
Richard F. Jacobs, M.D., Thomas G. Wells, M.D., Russell W. Steele, M.D., and Terry Yamauchi, M.D. Little Rock, Arkansas
CEFOTAX~M~, a third-generation cephalosporin with a broad spectrum of antimicrobiai activity against those bacterial pathogens that commonly cause bacterial meningitis in children, has been studied in children 1-6 and adults, 7,8 predominantly in Europe. Since its release in 1981, cefotaxime has received considerable attention and clinical use because of its excellent cerebrospinal fluid penetration, 5 Spectrum of activity,9, ~0 high levels of its major metabolite (desacetyl cefotaxime) in serum and CSF, 1~ and the proposed antimicrobial activity of this metabolite, ~2 resistance to hydrolysis by /3-1actamases,~ potential use as a single agent in children, ~-6 and lack of side effects. 14 When used to treat meningitis, either as a single agent or in combination with other antimicrobial
From the Department o f Pediatrics, Division o f Infectious Disease~Immunology, University o f Arkansas for Medical Sciences and Arkansas Children's Hospital. Submitted for publication Nov. 6, 1984; accepted Dec. 21, 1984. Reprint requests: R. F. Jaeobs, M.D., Arkansas Children's Hospital, 804 Wolfe St., Little Rock, A R 72202.
agents, cefotaxime eradicates most common neonatal and childhood pathogens. 1,4 Although studies have been too limited to allow the routine substitution of cefotaxime for standard therapyl the consensus has been that the use of CSF MBC MIC
Cerebrospinal fluid Minimum bactericidal concentration Minimum inhibitory concentration
]
cefotaxime is "as effective as" standard therapy. With the increasing use of cefotaxime and the desire by many clinicians to avoid potentially toxic antibiotics (chloramphenicol) or antibiotics with limited C S F concentrations (aminoglycosides), the prospective evaluation of this drug is necessary. We evaluated 50 children with culture-proved bacterial maningitis in a prospective, randomized trial comparing cefotaxime with standard therapy.
METHODS Fifty pediatric patients 1 week to 16 years old were admitted to Arkansas Children's Hospital between May 1983 and August 1984 with culture-proved bacterial The Journal o f P E D I A T R I C S
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The Journal of Pediatrics July 1985
Table I. Patient laboratory data
t Glucose (mg/dl) Standard therapy Mean 28.3 • 18.3 Range 0 to 62 Cefotaxime Mean 25.4 • 12.6 Range 0 to 89
Initial CSF Protein (mg/dl)
Repeat CSF WBC count (cells/mm 3)
Glucose (mg/dl)
Protein (mg/dl)
WBC count (cells/mm 3)
Initial blood WBC count (cells/mm 3)
230 • 145 62 to 700
6370 _+ 2319 240 to 21,920
46.8 • 20.4 24 to 81
88.3 + 27.3 22 to 182
3,832 _+ 1,627 1 to 29,000
14,763• 3,427 2,300 to 26,200
194 • 97 16 to 440
5962 _+ 2927 63 to 17,240
54.3 + 18.2 12 to 92
74.6 _+ 29.5 16 to 140
3,641 _+ 1,062 0 to 20,550
16,170• 4,829 3,500 to 34,500
No statisticallysignificantdifferencesbetweentherapy groups were found. *Repeat lumbarpunctureswere doneon day 2 of therapy in all 23 patientsreceivingcefotaximeand in 15 patientsreceivingstandard therapy. meningitis. Patients were prospectively randomized to receive cefotaxime (50 mg/kg/dose, given every 6 hours intravenously) or ampicillin (50 to 100 mg/kg/dose) and chloramphenicol (25 mg/kg/dose) given every 6 hours intravenously. The standard infusion rate for cefotaxime was 15 to 45 minutes. The study was reviewed and approved by the Institutional Review Board for Human Experimentation. Informed parental consent was obtained for all patients before inclusion in the study. Children with clinically suspected meningitis and purulent CSF were initially randomized to cefotaxime or standard therapy. CSF, blood, and urine cultures were processed and cultured in routine fashion by the clinical microbiology laboratory at Arkansas Children's Hospital. Nine Patients were initially included in the study but were Omitted from data analysis because of proved viral infection, sterile cultures, or bacterial antigen detection as the only positive assessment; None of the 50 patients analyzed had had documented hepatic, renal, cardiovascular, or central nervous system disease before the onset of meningitis. Antibiotics were administered as indicated above, excePt that gentamicin (2.5 mg/kg/dose, given every 8 or 12 hours intravenously) was substituted for chloramphenicol in the standard therapy group in two patients who were younger than 1 month at the time of their enrollment into the study. Serum gentamicin and chloramphenicol concentrations (peak and trough) were measured in all patients receiving standard therapy, and dosage adjustments were made as needed to assure therapeutic serum concentrations. Serum (6-hour pharmacokinetic profile) and CSF concentrations of parent compound and the desacetyl cefotaxime metabolite were measured in the patients receiving cefotaxime by high-performance liquid chromatography on day 2 of therapy. Repeat CSF chemical analysis, while blood cell count and differential, bactericidal titers, Gram stain, and culture were performed on aliquots of fluids obtained on day 2. After culture and sensitivity results were known, antibi-
otic regimens in the standard therapy group were modified to monotherapy or combination therapy appropriate for the organism. Meningitis caused by Streptococcus pneumoniae or Neisseria meningitidis was treated with penicillin G (250,000 U/kg/day, divided into four or six daily doses); chloramphenicol was discontinued in patients found to have Hemophilus influenzae susceptible to ampicillin. Routine laboratory monitoring was performed in all patients at the time of admission (before antibiotics), on days 4 to 5 of therapy, and at the end of antibiotic therapy. Laboratory studies included blood culture (before antibiotic dosing only), complete blood count with differential and platelet count, and serum levels of electrolytes, glucose, creatinine, and BUN. CSF analysis was performed in all patients receiving cefotaxime and also in those receiving standard therapy on day 2 of therapy when a lack of clinical improvement or presence of neurologic manifestations indicated potential therapy failure (n = 15). Hepatic enzymes and prothrombin and partial thromboplastin times were measured if clinically indicated. Urine was routinely obtained for urinalysis and culture before antibiotic dosing; all patients had a chest roentgenogram on the day of enrollment. Hemodynamic stability and perfusion were monitored in the intensive care unit for the initial 24 to 48 hours in most patients; arterial or central venous line placement, extended stay in intensive care, and vasopressor therapy were instituted as clinically indicated; nine patients required such intensive monitoring and therapy (five in the standard therapy group, four in the cefotaxime group). Routine Kirby-Bauer disk sensitivity was determined in all 50 CSF isolates; cefotaxime disk susceptibility testing used a 30 ~g disk. All H. influenzae isolates were tested for /3-1actamase production by the colorimetric cephalosporin assay; antibiotic susceptibility was further evaluated by a disk diffusion assay for ampicillin, chloramphenicol, and cefotaxime. The MIC and MBC were determined by a microtiter technique~; CSF bactericidal titers were per-
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Table lI. Microbiology and antibiotic sensitivity results
CeJbtaxirne
Organisms H. influenzae Mean Range ~-Lactamase (+) Mean Range /3-Lactamase ( - ) Mean Range S. pneumoniae Mean Range N. meningitidis Mean Range S. enteritidis Group B streptococci
Standard therapy
Cefotaxime
Total
15
14
29
5
10
3
5
1 3
4
10
5
3
1 0
CSF bactericidal titers*
(~g/ml)
MBC Ozg/ml)
0.024 • 0.026 0.001 to 0.320
0.064 ___0.054 0.004 to 1.0
1:180 • 172 1:8 to 1:512
0.041 + 0.036 0.002 to 0.2
0.084 + 0.071 0.004 to 1.0
1:64 + 32 1:8 to 1:128
0.006 • 0.005 0.001 to 0.32
0.040 -+_ 0.027 0.004 to 0.8
1:220 _+180 1:64 to 1:512
0.062 _+ 0.034 0.004 to 0.8
0.240 • 0.124 0.008 to 2.0
1:160 • 154 1:8 to 1:512
2
0.057 • 0.088 0.004 to 0.16 0.0004
0.283 • 0.448 0.016 to 0.8 0.07
1:213 • 258 1:64 to 1:512 1 : 1024
3
t
t
t
M1C
9
20
8
8
*Only for patients receivingcefotaxime. "~Notdone; antibiotic susceptibility by disk diffusion analysis only. formed on all patients receiving cefotaxime as previously described. 16 At the end of therapy, all patients were evaluated for auditory deficits. Impedance audiometry was performed on all older infants and children; an auditory evoked E E G was performed on children younger than 6 months. Developmental assessment, head circumference measurement, vision screening, and a complete neurologic examination were performed before discharge and at 2 weeks and 2 months after discharge. Repeat audiologic evaluation was performed at 2 months after discharge. An E E G was performed on all patients with clinical seizures; patients discharged who continued anticonvulsant therapy and who had no history of prior seizure activity were considered to have seizures as a complication of meningitis. Patients were reevaluated longitudinally to determine whether this seizure activity persisted as a permanent sequela. Cranial ultrasonography or computed tomography was used to confirm clinically suspected intracranial diseases. All results are expressed as the mean _+ 1 SD. Analysis of the data for significance between the therapy groups was by unpaired, two-tailed Student t tests and was confirmed by the Mann-Whitney U test or chi-square analysis where indicated. 17 The accepted level of significance was P <0.05. RESULTS Analysis of demographic characteristics of the two groups revealed no statistically significant differences.
Mean age of the patients receiving cefotaxime (n = 23, 14 boys) was 24.4 +_ 36.4 months (range 1 month to 12 years); mean age of patients receiving standard therapy (n -- 27, 20 boys) was 16.6 +_ 35.9 months (range 1 week to 16 years). Laboratory studies of blood and initial and repeat C S F samples revealed no statistically significant differences between the two groups (Table I). C S F cultures on the repeat lumbar puncture were sterile in all patients (cefotaxime, 23; standard therapy, 15). The rate of ampicillin-resistant H. influenzae was 34% (Table II). All 50 isolates were susceptible to cefotaxime; one isolate of H. influenzae was ~-lactamase negative on repeat testing but was resistant to ampicillin as determined by disk diffusion and M I C and M B C analysis; no H. influenzae strains were resistant to chloramphenicol. One strain of S. pneumoniae was found to be relatively resistant to penicillin ( M I C = 0.8 ~ g / m l ) ; both Salmonella isolates were susceptible to all study antibiotics. Ten of the 27 patients receiving standard therapy had positive bacterial cultures from one or more sites in addition to the CSF. Of these 10 patients, seven had meningitis and bacteremia (H. influenzae, six, group B streptococcus, one), one had S. pneumoniae meningitis and the same organism isolated from a middle ear culture, one had Salmonella enteritidis isolated from CSF, blood, and stool, and one patient with N. meningitidis meningitis and bacteremia had a concurrent Escherichia coli urinary tract infection. Twelve of the 23 patients receiving cefotaxime
132
Jacobs et al.
had positive cultures from one or more sites in addition to the CSF. These included nine patients with meningitis and bacteremia (H. influenzae, six, IV. meningitidis, two, S. pneumoniae, one), one had S. pneumoniae meningitis and a positive culture from middle ear fluid, S. enteritidis was isolated from CSF and stool in one patient, and one patient had H. influenzae meningitis, baeteremia, and a concurrent E. coli urinary tract infection. The mean MIC for cefotaxime against the/3-1actamasepositive H. influenzae isolates were significantly higher than for t3-1actamase-negative isolates (P <0.05). The clinical cure rate for the cefotaxime group was 100% with no relapses; the clinical cure rate for the standard therapy group was 96% (P >0.05). One patient in the standard therapy group with overwhelming H. influenzae meningitis and sepsis died on day 2 of therapy, and the patient receiving therapy for 21 days with ampicillin and chloramphenicol for S. enteritidis meningitis was readmitted to the hospital 3 months later with S. enteritidis meningitis. The antibiotic susceptibility pattern and serotyping on the two Salmonella isolates were identical. This patient had developed hydrocephalus, spasticity, seizure activity, and evidence of eerebritis as determined by cranial CT. The rates of survival without detectable sequelae were similar, 78% in the cefotaxime group and 77% in the standard therapy group. Duration of therapy was also similar for the cefotaxime and standard therapy groups: 11.1 _+ 2.4 and 11.9 _+ 3.9 days, respectively, with a range of 10 to 21 days for both; duration of fever was similar at 4.7 _+ 2.6 days (range 1 to 14 days) and 5.6 _+ 2.9 days (range 2 to 17 days), respectively. No adverse drug reactions were observed in any of the 50 patients, No leukopenia, thrombocytopenia, or evidence of clinical bleeding was found; disseminated intravascular coagulopathy was documented in the one fatal, overwhelming infection but was believed to be related to the underlying disease. No evidence of thrombophlebitis was observed. Two patients receiving cefotaxime had mild diarrhea. One patient in the standard therapy group developed evidence of acute tubular necrosis associated with elevated BUN and creatinine concentrations; renal function subsequently returned to normal. Detectable complications and sequelae occurred in 10 of the 49 survivors. In the standard therapy group, one patient developed seizures alone; three patients developed seizure activity in association with hydrocephalus, subdural effusions, and evidence of a right frontal lobe infarct, respectively; one patient developed spasticity. All of these patients had evidence of developmental delay as compared with their premeningitis medical history evaluation, and two had moderate hearing loss. In the cefotaxime group, two patients developed seizure activity, two had subdural
The Journal of Pediatrics July 1985
effusions, and one had profound hearing loss. Four of these five patients had developmental delay. All patients in our study have been observed for at least 3 months, and reevaluated. Although the complication of seizures has not been followed up long enough to allow it to be classified as a sequela, all of these patients had either hearing loss, hydrocephalus, spasticity, or developmental delay during the brief follow-up. Tl~e patients with developmental delay have not yet been evaluated by detailed psychometric testing. Therefore, although these were the only patients with complications, permanent sequelae have not yet been identified. Despite the lack of long-term follow-up data, the therapy regimens were similar for rates of sequelae or complications. DISCUSSION Previous studies have demonstrated the efficacy of cefotaxime alone or in combination with other antibiotics in the treatment of bacterial meningitis in neonates, children, and adults, vs With the exception of our study and an ongoing larger comparison, ~8there has been a paucity of prospective data with follow-up to evaluate cefotaxime vs standard therapy. Our rates of clinical response, eradication of organisms, and postmeningitis sequelae have demonstrated that cefotaxime is as effective as standard therapy and has no associated side effects or adverse reactions. Sterilization of the CSF was documented in all of the patients who received cefotaxime on day 2 of therapy. With a mean concentration of 6.2 #g/ml cefotaxime (9.4% penetration) and 5.6 #g/ml desacetyl cefotaxime (28.9% penetration) in the CSF, the MIC and MBC for all causative organisms were several times higher. The desacetyl cefotaxime metabolite, found in increased concentrations in CSF, has been demonstrated to have antimicrobial activity in vitro. J2 The mean concentration of this metabolite exceeded that of the parent compound, suggesting either better penetration through inflamed meninges or accumulation in CSF. With a single concentration value for each, no statement can be made regarding these kinetics. The discrepancy between measured concentrations vs MIC and MBC results and the high CSF bactericidal titers adds support to the antimicrobial activity of this compound. This increased penetration or accumulation with antimicrobial activity of the desacetyl metabolite may offer an added benefit to cefotaxime over other members of this class of antibiotics for completion of therapy when meningeal inflammation subsides. It may also be a contributing factor to the excellent results in children and adults with meningitis. ~-8,~g The lack of optimal activity of third-generation cephalosporins against Listeria monocytogenes and enterococci (group D streptococci) ~9 warrants caution in the use of cefotaxime as a single agent in neonates or younger infants
Volume 107 Number 1 2 to 6 weeks old, in whom such infections commonly occur. 2~ A combination of a penicillin (ampicillin) and a cephalosporin such as cefotaxime would seem efficacious in this age population. Beyond age 6 weeks and with a G r a m stain not demonstrating L. monocytogenes or grampositive cocci (compatible with group B or D streptococci), cefotaxime as a single drug is an attractive alternative to standard therapy. If the prevalence of aminoglycosideresistant enteric gram-negative organisms, ampicillin- or chloramphenicol-resistant H. influenzae, and penicillinresistant S. pneumoniae continues to increase, the use of cephalosporins such as cefotaxime may become standard therapy. Continued caution, aggressive monitoring, and close follow-up are still mandatory for Salmonella meningitis because of its predisposition to severity, sequelae, and relapse. 2~ The continued necessity for monitoring serum gentamicin and chloramphenicol concentrations with dosage adjustments in severely ill children was apparent in this study. The lack of adverse reactions with cefotaxime reflects its relatively wide therapeutic index. Our initial evaluation and subsequent follow-up revealed comparable rates of complications and sequelae in both groups. Other studies comparing patients with meningitis who received cefotaxime with historical controls receiving standard therapy or ampicillin and cefotaxime have suggested a decrease in sequelae in children who receive therapy with cefotaxime. 22 Our data indicate that cefotaxime was "as effective as" standard therapy in the clinical cure rate and comparable in the rate of subsequent complications and sequelae. We thank Billie Marmer, R.N., Ann Augustine, R.N., Allen Brown, Pharm.D., Gregory Kearns, Pharm.D., and the pediatric housestaff at the Arkansas Children's Hospital for their support. REFERENCES
1. Belohradsky BH, Geiss D, Margret W, Bruch K, Kafetzis DA, Peters G: Intravenous cefotaxime in children with bacterial meningitis. Lancet 1:61, 1980. 2. Papadatos C J, Kafetzis DA, Kanarios J: Cefotaxime in the treatment of severe paediatric infections, J Antimicrob Chemother 6(suppl):243, 1980. 3. Roos R, Margret W, Trujillo H, Kafetzis DA, Papadatos C J, Hattinberg HMV, Belohradsky BH, Bruch K: Multizentrische studie uber cefotaxime bei meningitis and sepsis imkindesalter. Klinische ergebnisse, serum-pharmakokinetik und liquor-spiegel. Infection 8(suppl):S 501, 1980. 4. Borderon JC, Prieur D, Huguet B: Concentrations du cefotaxime dans le liquide cephaloachidien chez des enfants atteients de meningite purulente. Nouv Presse Med 10:580, 1981. 5. Kafetzis DA, Brater DC, Kapiki AN, Papas CV, Dellagrammaticas H, Papadatos C J: Treatment of severe neonatal infections with cefotaxime. Efficacy and pharmacokinetics. J PEDIATR 3:483, 1982.
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6. Begue P, Floret D, Raynaud E J, Sarlangues J, Teyssier G, Safran C: Pharmacokinetics and clinical evaluation of eefotaxime in children suffering with purulent meningitis. Program and abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., October 1984, p 132. 7. Mullaney DT, John JF: Cefotaxime therapy of serious bacterial infection in adults. Antimicrob Agents Chemother 21:421, 1982. 8. Mullaney DT, John JF: Cefotaxime therapy. Evaluations of its effect on bacterial meningitis, CSF drug levels, and bactericidal activity. Arch Intern Med 143:1705, 1983. 9. Drasar FA, Farrell W, Howard A J, Hince C, Leung T, Williams JD: Activity of HR756 against Haemophilus influenzae, Bacteroides fragilis and gram-negative rods. J Antimicrob Chemother 4:445, 1978. 10. Hamilton-Miller JMT, Brumfitt W, Reynolds AV: Cefotaxime (HR756) a new cephalosporin with exceptional broadspectrum activity in vitro. J Antimicrob Chemother 4:437, 1978. 11. Dudley MN, Barriere SL: Cefotaxime: Microbiology, pharmacology, and clinical use. Clin Pharmaeol 1:114, 1982. 12. Wise R, Wills P J, Andrews JM, Bedford KA: Activity of the cefotaxime (HR756) desacetyl metabolite compared with those of cefotaxime and other cephalosporins. Antimicrob Agents Chemother 17:84, 1980. 13. Fu KP, Neu NC: The comparative ~-lactamase resistance and inhibitory activity of 1-oxa cephalosporin, cefoxitin, and cefotaxime. J Antibiot 32:909, 1979. 14. Young JPW, Husson JM, Bruch K, Blomer R, Savopoulos C: The evaluation of efficacy and safety of cefotaxime: A review of 2500 cases. J Antimicrob Chemother 6(suppl A):293, 1980. 15. Gavan TL, Barry AL: Microdilution test procedures. In Lennette EH, Balows A, Hausler WJ Jr, Truant JP, editors: Manual for clinical microbiology. Washington, DC, 1980, American Society for Microbiology, pp 459-62. 16. Schaad UB, McCracken GH Jr, Loock CA, Thomas ML: Pharmacokinetics and bacteriologic efficacy of moxalactam, cefotaxime, cefoperazone, and Rocephin in experimental bacterial meningitis. J Infect Dis 143:156, 1981. 17. Dixon W J, Massey FJ Jr: Introduction to statistical analysis, ed 3. New York, 1969, McGraw-Hill Book Co. 18. Odio CM, Faingezicht 1, Mohs E, Salas JL, McCracken GH Jr: Cefotaxime versus conventional therapy for bacterial meningitis in infants and children. Program and abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., October 1984, p 132. 19. Bradsher RW, Ulmer WC: B-lactam antibiotic susceptibility of bacteria responsible for bacterial meningitis. Chemotherapy 29:213, 1983. 20. Baumgartner E, Augustine A, Steele RW: Bacterial meningitis in older neonates. Am J Dis Child 137:1052, 1983. 21. Rabinowitz SG, MacLeod NR: Salmonella meningitis. Am J Dis Child 123:259, 1972. 22. Lapointe JR, Belivau C, Chicoine L, Joncas JH: A comparison of ampicillin-cefotaxime and ampicillin-chloramphenieol in childhood bacterial meningitis: An experience in fifty-five patients. J Antimicrob Chemother 14(suppl B):167, 1984.
A prospective randomized comparison of cefotaxime vs ampicillin and chloramphenicol for bacterial meningitis in children Fifty children with bacterial meningitis were prospectively randomized to receive ceJotaxime (50 mg/kg/dose every 6 hours) or ampieillin and ehloramphenicol in standard doses. Twenty-three patients received cefotaxime and 27 received standard therapy. Bacterial isolates included- Haemophilus influenzae (29), Streptococcus pneumoniae (eight), Neisseria meningitidis (eight), group B streptococci (three), and Salmonella enteritidis (two). Ten (34 %) o f the H. influenzae isolates were resistant to ampicillin, nine on the basis o f ~-laetamase production. All strains were susceptible to cefotaxime. Clinical cure rates for the cefotaxime (100%) and standard therapy (96%) groups Were similar," survival without detectable sequelae was Similar, at 78% and 77%, respectively. The duration o f therapy, 11.1 +_ 2.4 days (range 10 to 21 days) vs 11.9 +_ 3.9 days (range 10 to 21 days), and days to defervescence, 4.7 +_ 2:6 days (range 1 to 14 days) vs 5.6 + 2.9 days (range 2 to 17 days), were similar in the cefotaxime and standard therapy groups, respectively. No adverse drug reactions or side effects were noted in either group. Cefotaxime was found to be as safe and effective as standard therapy for the treatment o f bacterial meningitis in children. (J PEt)I.~TR 107:i29, 1985)
Richard F. Jacobs, M.D., Thomas G. Wells, M.D., Russell W. Steele, M.D., and Terry Yamauchi, M.D. Little Rock, Arkansas
CEFOTAX~M~, a third-generation cephalosporin with a broad spectrum of antimicrobiai activity against those bacterial pathogens that commonly cause bacterial meningitis in children, has been studied in children 1-6 and adults, 7,8 predominantly in Europe. Since its release in 1981, cefotaxime has received considerable attention and clinical use because of its excellent cerebrospinal fluid penetration, 5 Spectrum of activity,9, ~0 high levels of its major metabolite (desacetyl cefotaxime) in serum and CSF, 1~ and the proposed antimicrobial activity of this metabolite, ~2 resistance to hydrolysis by /3-1actamases,~ potential use as a single agent in children, ~-6 and lack of side effects. 14 When used to treat meningitis, either as a single agent or in combination with other antimicrobial
From the Department o f Pediatrics, Division o f Infectious Disease~Immunology, University o f Arkansas for Medical Sciences and Arkansas Children's Hospital. Submitted for publication Nov. 6, 1984; accepted Dec. 21, 1984. Reprint requests: R. F. Jaeobs, M.D., Arkansas Children's Hospital, 804 Wolfe St., Little Rock, A R 72202.
agents, cefotaxime eradicates most common neonatal and childhood pathogens. 1,4 Although studies have been too limited to allow the routine substitution of cefotaxime for standard therapyl the consensus has been that the use of CSF MBC MIC
Cerebrospinal fluid Minimum bactericidal concentration Minimum inhibitory concentration
]
cefotaxime is "as effective as" standard therapy. With the increasing use of cefotaxime and the desire by many clinicians to avoid potentially toxic antibiotics (chloramphenicol) or antibiotics with limited C S F concentrations (aminoglycosides), the prospective evaluation of this drug is necessary. We evaluated 50 children with culture-proved bacterial maningitis in a prospective, randomized trial comparing cefotaxime with standard therapy.
METHODS Fifty pediatric patients 1 week to 16 years old were admitted to Arkansas Children's Hospital between May 1983 and August 1984 with culture-proved bacterial The Journal o f P E D I A T R I C S
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The Journal of Pediatrics July 1985
Table I. Patient laboratory data
t Glucose (mg/dl) Standard therapy Mean 28.3 • 18.3 Range 0 to 62 Cefotaxime Mean 25.4 • 12.6 Range 0 to 89
Initial CSF Protein (mg/dl)
Repeat CSF WBC count (cells/mm 3)
Glucose (mg/dl)
Protein (mg/dl)
WBC count (cells/mm 3)
Initial blood WBC count (cells/mm 3)
230 • 145 62 to 700
6370 _+ 2319 240 to 21,920
46.8 • 20.4 24 to 81
88.3 + 27.3 22 to 182
3,832 _+ 1,627 1 to 29,000
14,763• 3,427 2,300 to 26,200
194 • 97 16 to 440
5962 _+ 2927 63 to 17,240
54.3 + 18.2 12 to 92
74.6 _+ 29.5 16 to 140
3,641 _+ 1,062 0 to 20,550
16,170• 4,829 3,500 to 34,500
No statisticallysignificantdifferencesbetweentherapy groups were found. *Repeat lumbarpunctureswere doneon day 2 of therapy in all 23 patientsreceivingcefotaximeand in 15 patientsreceivingstandard therapy. meningitis. Patients were prospectively randomized to receive cefotaxime (50 mg/kg/dose, given every 6 hours intravenously) or ampicillin (50 to 100 mg/kg/dose) and chloramphenicol (25 mg/kg/dose) given every 6 hours intravenously. The standard infusion rate for cefotaxime was 15 to 45 minutes. The study was reviewed and approved by the Institutional Review Board for Human Experimentation. Informed parental consent was obtained for all patients before inclusion in the study. Children with clinically suspected meningitis and purulent CSF were initially randomized to cefotaxime or standard therapy. CSF, blood, and urine cultures were processed and cultured in routine fashion by the clinical microbiology laboratory at Arkansas Children's Hospital. Nine Patients were initially included in the study but were Omitted from data analysis because of proved viral infection, sterile cultures, or bacterial antigen detection as the only positive assessment; None of the 50 patients analyzed had had documented hepatic, renal, cardiovascular, or central nervous system disease before the onset of meningitis. Antibiotics were administered as indicated above, excePt that gentamicin (2.5 mg/kg/dose, given every 8 or 12 hours intravenously) was substituted for chloramphenicol in the standard therapy group in two patients who were younger than 1 month at the time of their enrollment into the study. Serum gentamicin and chloramphenicol concentrations (peak and trough) were measured in all patients receiving standard therapy, and dosage adjustments were made as needed to assure therapeutic serum concentrations. Serum (6-hour pharmacokinetic profile) and CSF concentrations of parent compound and the desacetyl cefotaxime metabolite were measured in the patients receiving cefotaxime by high-performance liquid chromatography on day 2 of therapy. Repeat CSF chemical analysis, while blood cell count and differential, bactericidal titers, Gram stain, and culture were performed on aliquots of fluids obtained on day 2. After culture and sensitivity results were known, antibi-
otic regimens in the standard therapy group were modified to monotherapy or combination therapy appropriate for the organism. Meningitis caused by Streptococcus pneumoniae or Neisseria meningitidis was treated with penicillin G (250,000 U/kg/day, divided into four or six daily doses); chloramphenicol was discontinued in patients found to have Hemophilus influenzae susceptible to ampicillin. Routine laboratory monitoring was performed in all patients at the time of admission (before antibiotics), on days 4 to 5 of therapy, and at the end of antibiotic therapy. Laboratory studies included blood culture (before antibiotic dosing only), complete blood count with differential and platelet count, and serum levels of electrolytes, glucose, creatinine, and BUN. CSF analysis was performed in all patients receiving cefotaxime and also in those receiving standard therapy on day 2 of therapy when a lack of clinical improvement or presence of neurologic manifestations indicated potential therapy failure (n = 15). Hepatic enzymes and prothrombin and partial thromboplastin times were measured if clinically indicated. Urine was routinely obtained for urinalysis and culture before antibiotic dosing; all patients had a chest roentgenogram on the day of enrollment. Hemodynamic stability and perfusion were monitored in the intensive care unit for the initial 24 to 48 hours in most patients; arterial or central venous line placement, extended stay in intensive care, and vasopressor therapy were instituted as clinically indicated; nine patients required such intensive monitoring and therapy (five in the standard therapy group, four in the cefotaxime group). Routine Kirby-Bauer disk sensitivity was determined in all 50 CSF isolates; cefotaxime disk susceptibility testing used a 30 ~g disk. All H. influenzae isolates were tested for /3-1actamase production by the colorimetric cephalosporin assay; antibiotic susceptibility was further evaluated by a disk diffusion assay for ampicillin, chloramphenicol, and cefotaxime. The MIC and MBC were determined by a microtiter technique~; CSF bactericidal titers were per-
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Cefotaxime for bacterial meningitis
13 1
Table lI. Microbiology and antibiotic sensitivity results
CeJbtaxirne
Organisms H. influenzae Mean Range ~-Lactamase (+) Mean Range /3-Lactamase ( - ) Mean Range S. pneumoniae Mean Range N. meningitidis Mean Range S. enteritidis Group B streptococci
Standard therapy
Cefotaxime
Total
15
14
29
5
10
3
5
1 3
4
10
5
3
1 0
CSF bactericidal titers*
(~g/ml)
MBC Ozg/ml)
0.024 • 0.026 0.001 to 0.320
0.064 ___0.054 0.004 to 1.0
1:180 • 172 1:8 to 1:512
0.041 + 0.036 0.002 to 0.2
0.084 + 0.071 0.004 to 1.0
1:64 + 32 1:8 to 1:128
0.006 • 0.005 0.001 to 0.32
0.040 -+_ 0.027 0.004 to 0.8
1:220 _+180 1:64 to 1:512
0.062 _+ 0.034 0.004 to 0.8
0.240 • 0.124 0.008 to 2.0
1:160 • 154 1:8 to 1:512
2
0.057 • 0.088 0.004 to 0.16 0.0004
0.283 • 0.448 0.016 to 0.8 0.07
1:213 • 258 1:64 to 1:512 1 : 1024
3
t
t
t
M1C
9
20
8
8
*Only for patients receivingcefotaxime. "~Notdone; antibiotic susceptibility by disk diffusion analysis only. formed on all patients receiving cefotaxime as previously described. 16 At the end of therapy, all patients were evaluated for auditory deficits. Impedance audiometry was performed on all older infants and children; an auditory evoked E E G was performed on children younger than 6 months. Developmental assessment, head circumference measurement, vision screening, and a complete neurologic examination were performed before discharge and at 2 weeks and 2 months after discharge. Repeat audiologic evaluation was performed at 2 months after discharge. An E E G was performed on all patients with clinical seizures; patients discharged who continued anticonvulsant therapy and who had no history of prior seizure activity were considered to have seizures as a complication of meningitis. Patients were reevaluated longitudinally to determine whether this seizure activity persisted as a permanent sequela. Cranial ultrasonography or computed tomography was used to confirm clinically suspected intracranial diseases. All results are expressed as the mean _+ 1 SD. Analysis of the data for significance between the therapy groups was by unpaired, two-tailed Student t tests and was confirmed by the Mann-Whitney U test or chi-square analysis where indicated. 17 The accepted level of significance was P <0.05. RESULTS Analysis of demographic characteristics of the two groups revealed no statistically significant differences.
Mean age of the patients receiving cefotaxime (n = 23, 14 boys) was 24.4 +_ 36.4 months (range 1 month to 12 years); mean age of patients receiving standard therapy (n -- 27, 20 boys) was 16.6 +_ 35.9 months (range 1 week to 16 years). Laboratory studies of blood and initial and repeat C S F samples revealed no statistically significant differences between the two groups (Table I). C S F cultures on the repeat lumbar puncture were sterile in all patients (cefotaxime, 23; standard therapy, 15). The rate of ampicillin-resistant H. influenzae was 34% (Table II). All 50 isolates were susceptible to cefotaxime; one isolate of H. influenzae was ~-lactamase negative on repeat testing but was resistant to ampicillin as determined by disk diffusion and M I C and M B C analysis; no H. influenzae strains were resistant to chloramphenicol. One strain of S. pneumoniae was found to be relatively resistant to penicillin ( M I C = 0.8 ~ g / m l ) ; both Salmonella isolates were susceptible to all study antibiotics. Ten of the 27 patients receiving standard therapy had positive bacterial cultures from one or more sites in addition to the CSF. Of these 10 patients, seven had meningitis and bacteremia (H. influenzae, six, group B streptococcus, one), one had S. pneumoniae meningitis and the same organism isolated from a middle ear culture, one had Salmonella enteritidis isolated from CSF, blood, and stool, and one patient with N. meningitidis meningitis and bacteremia had a concurrent Escherichia coli urinary tract infection. Twelve of the 23 patients receiving cefotaxime
132
Jacobs et al.
had positive cultures from one or more sites in addition to the CSF. These included nine patients with meningitis and bacteremia (H. influenzae, six, IV. meningitidis, two, S. pneumoniae, one), one had S. pneumoniae meningitis and a positive culture from middle ear fluid, S. enteritidis was isolated from CSF and stool in one patient, and one patient had H. influenzae meningitis, baeteremia, and a concurrent E. coli urinary tract infection. The mean MIC for cefotaxime against the/3-1actamasepositive H. influenzae isolates were significantly higher than for t3-1actamase-negative isolates (P <0.05). The clinical cure rate for the cefotaxime group was 100% with no relapses; the clinical cure rate for the standard therapy group was 96% (P >0.05). One patient in the standard therapy group with overwhelming H. influenzae meningitis and sepsis died on day 2 of therapy, and the patient receiving therapy for 21 days with ampicillin and chloramphenicol for S. enteritidis meningitis was readmitted to the hospital 3 months later with S. enteritidis meningitis. The antibiotic susceptibility pattern and serotyping on the two Salmonella isolates were identical. This patient had developed hydrocephalus, spasticity, seizure activity, and evidence of eerebritis as determined by cranial CT. The rates of survival without detectable sequelae were similar, 78% in the cefotaxime group and 77% in the standard therapy group. Duration of therapy was also similar for the cefotaxime and standard therapy groups: 11.1 _+ 2.4 and 11.9 _+ 3.9 days, respectively, with a range of 10 to 21 days for both; duration of fever was similar at 4.7 _+ 2.6 days (range 1 to 14 days) and 5.6 _+ 2.9 days (range 2 to 17 days), respectively. No adverse drug reactions were observed in any of the 50 patients, No leukopenia, thrombocytopenia, or evidence of clinical bleeding was found; disseminated intravascular coagulopathy was documented in the one fatal, overwhelming infection but was believed to be related to the underlying disease. No evidence of thrombophlebitis was observed. Two patients receiving cefotaxime had mild diarrhea. One patient in the standard therapy group developed evidence of acute tubular necrosis associated with elevated BUN and creatinine concentrations; renal function subsequently returned to normal. Detectable complications and sequelae occurred in 10 of the 49 survivors. In the standard therapy group, one patient developed seizures alone; three patients developed seizure activity in association with hydrocephalus, subdural effusions, and evidence of a right frontal lobe infarct, respectively; one patient developed spasticity. All of these patients had evidence of developmental delay as compared with their premeningitis medical history evaluation, and two had moderate hearing loss. In the cefotaxime group, two patients developed seizure activity, two had subdural
The Journal of Pediatrics July 1985
effusions, and one had profound hearing loss. Four of these five patients had developmental delay. All patients in our study have been observed for at least 3 months, and reevaluated. Although the complication of seizures has not been followed up long enough to allow it to be classified as a sequela, all of these patients had either hearing loss, hydrocephalus, spasticity, or developmental delay during the brief follow-up. Tl~e patients with developmental delay have not yet been evaluated by detailed psychometric testing. Therefore, although these were the only patients with complications, permanent sequelae have not yet been identified. Despite the lack of long-term follow-up data, the therapy regimens were similar for rates of sequelae or complications. DISCUSSION Previous studies have demonstrated the efficacy of cefotaxime alone or in combination with other antibiotics in the treatment of bacterial meningitis in neonates, children, and adults, vs With the exception of our study and an ongoing larger comparison, ~8there has been a paucity of prospective data with follow-up to evaluate cefotaxime vs standard therapy. Our rates of clinical response, eradication of organisms, and postmeningitis sequelae have demonstrated that cefotaxime is as effective as standard therapy and has no associated side effects or adverse reactions. Sterilization of the CSF was documented in all of the patients who received cefotaxime on day 2 of therapy. With a mean concentration of 6.2 #g/ml cefotaxime (9.4% penetration) and 5.6 #g/ml desacetyl cefotaxime (28.9% penetration) in the CSF, the MIC and MBC for all causative organisms were several times higher. The desacetyl cefotaxime metabolite, found in increased concentrations in CSF, has been demonstrated to have antimicrobial activity in vitro. J2 The mean concentration of this metabolite exceeded that of the parent compound, suggesting either better penetration through inflamed meninges or accumulation in CSF. With a single concentration value for each, no statement can be made regarding these kinetics. The discrepancy between measured concentrations vs MIC and MBC results and the high CSF bactericidal titers adds support to the antimicrobial activity of this compound. This increased penetration or accumulation with antimicrobial activity of the desacetyl metabolite may offer an added benefit to cefotaxime over other members of this class of antibiotics for completion of therapy when meningeal inflammation subsides. It may also be a contributing factor to the excellent results in children and adults with meningitis. ~-8,~g The lack of optimal activity of third-generation cephalosporins against Listeria monocytogenes and enterococci (group D streptococci) ~9 warrants caution in the use of cefotaxime as a single agent in neonates or younger infants
Volume 107 Number 1 2 to 6 weeks old, in whom such infections commonly occur. 2~ A combination of a penicillin (ampicillin) and a cephalosporin such as cefotaxime would seem efficacious in this age population. Beyond age 6 weeks and with a G r a m stain not demonstrating L. monocytogenes or grampositive cocci (compatible with group B or D streptococci), cefotaxime as a single drug is an attractive alternative to standard therapy. If the prevalence of aminoglycosideresistant enteric gram-negative organisms, ampicillin- or chloramphenicol-resistant H. influenzae, and penicillinresistant S. pneumoniae continues to increase, the use of cephalosporins such as cefotaxime may become standard therapy. Continued caution, aggressive monitoring, and close follow-up are still mandatory for Salmonella meningitis because of its predisposition to severity, sequelae, and relapse. 2~ The continued necessity for monitoring serum gentamicin and chloramphenicol concentrations with dosage adjustments in severely ill children was apparent in this study. The lack of adverse reactions with cefotaxime reflects its relatively wide therapeutic index. Our initial evaluation and subsequent follow-up revealed comparable rates of complications and sequelae in both groups. Other studies comparing patients with meningitis who received cefotaxime with historical controls receiving standard therapy or ampicillin and cefotaxime have suggested a decrease in sequelae in children who receive therapy with cefotaxime. 22 Our data indicate that cefotaxime was "as effective as" standard therapy in the clinical cure rate and comparable in the rate of subsequent complications and sequelae. We thank Billie Marmer, R.N., Ann Augustine, R.N., Allen Brown, Pharm.D., Gregory Kearns, Pharm.D., and the pediatric housestaff at the Arkansas Children's Hospital for their support. REFERENCES
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