INFU/PARA: Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis

• Sponsor: University of Helsinki (Other)
• Overall Status: Completed
• CT.gov ID: NCT01540838
• Collaborator: Foundation for Paediatric Research, Finland (Other)
• Enrollment: 375
• Location: 1
• Arms: 2
• Actual Duration (Months): 60
• Patients Per Site Per Month: 6.2

Study Details

Study Description

Brief Summary

The main purpose of this trial is to test if mortality of childhood bacterial meningitis can be reduced by slow, continuous infusion of cefotaxime initially, instead of the traditional bolus administration four times daily (qid), combined with high-dose paracetamol orally, when both treatments are executed for the first 4 days. The series will be collected at Hospital Pediátrico David Bernardino, Luanda, Angola.

The recruitment of patients begins, the conditions permitting, in early 2012. The criteria for patient participation is a child at the age of 2 months to 15 years who presents with the symptoms and signs suggestive of bacterial meningitis, for whom a lumbar puncture is performed, and the cerebrospinal fluid analysis suggests bacterial meningitis.

Condition or Disease	Intervention/Treatment	Phase
Bacterial Meningitis	Drug: Infusion with paracetamol; Drug: Bolus without paracetamol	Phase 4

Detailed Description

The principal objective of the study is to examine if mortality of childhood bacterial meningitis can be reduced by slow continuous infusion of cefotaxime combined with high-dose paracetamol orally for the first 4 days (instead of the traditional qid administration of cefotaxime without concomitant paracetamol). Children qualifying for entry (see criteria below), whose guardian has given informed consent,will be randomized into 2 treatment arms (see details below)and receive the treatments in a double blind fashion (see details below). Primary and secondary outcomes (detailed below) will be evaluated according to predefined criteria and time points (see below).

Results will be analyzed for all patients in ITT datasets and in prespecified subgroups (etiology, nutritional status, etc.) in both crude and adjusted analysis. The efficacy results will be expressed as OR with 95% confidence intervals.

Study Design

• Study Type: Interventional
• Actual Enrollment: 375 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis, Especially of Pneumococcal Meningitis, in Angola.
• Actual Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Feb 1, 2017
• Actual Study Completion Date: Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Infusion with paracetamol Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen)	Drug: Infusion with paracetamol; The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.; Other Names: paracetamol=acetaminophen
Active Comparator: Bolus with placebo Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol	Drug: Bolus without paracetamol; The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.; Other Names: Paracetamol=acetaminophen

Outcome Measures

Primary Outcome Measures

1. Day 7 Mortality [On day 7 from the institution of treatment]

   All patients who had received at least one dose of treatment and were dead on day 7 from the institution of treatment on day 1.

Secondary Outcome Measures

1. All Deaths During Hospital Stay [The outcome was assessed each day until the patient was discharged from the hospital. The longest hospital stay was 84 days, while the last death occurred 39 days after treatment initiation.]

   All patients who had received at least one dose of treatment and died during the hospital stay.

2. Status on the Modified Glasgow Outcome Scale [Examined at discharge from hospital, except for hearing evaluations which were performed at earliest seven days since the institution of treatment, during the hospital stay. The longest hospital stay was 84 days.]

   Scores on the modified Glasgow Outcome Scale which range from a maximum of 5 (best) to a minimum of 1 (worst) points. The Glasgow Outcome Scale categorizes the outcome after brain injury into five categories, based on the level and severeness of disability. As hearing impairment is one of the most common sequelae of bacterial meningitis, an assessment of hearing should be included when estimating the grade of disability. Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately.

3. Death or Any Neurological Sequelae on Day 7 [Examined on day 7 since institution of treatment.]

   Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.

4. A Change in Hearing Threshold Compared to the First Test Result [Hearing thresholds obtained during any of the first three days after hospital admission were compared with hearing thresholds obtained on day seven or later, during the hospital stay. The longest hospital stay was 84 days.]

   Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. The better ear's hearing threshold, obtained on admission or shortly thereafter, was compared with the better ear's hearing threshold obtained at earliest after one week of treatment.

5. Death or Severe Neurological Sequelae on Day 7 [Examined on day 7 since institution of treatment]

   Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation

6. Number of Participants With Deafness [This outcome includes hearing thresholds determined at earliest seven days after the institution of treatment, during the hospital stay. The longest hospital stay was 84 days.]

   Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. Deafness was defined as a hearing threshold >80 dB in the better ear.

7. Death or Any Neurological Sequelae at Discharge From Hospital. [Examined at discharge from hospital. The longest hospital stay was 84 days.]

   Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.

8. Death or Severe Neurological Sequelae at Discharge [Examined at discharge from hospital. The longest hospital stay was 84 days.]

   Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Months to 15 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Eligibility criteria:

The study entry is assessed for all children at age 2 months - 15 years who present at these centers with the symptoms and signs suggestive of bacterial meningitis (BM), and to whom lumbar puncture is performed.

Inclusion criteria:

All patients whose cerebrospinal fluid (CSF) turns out to be cloudy, positive by Gram staining or latex agglutination, or shows at least 50 leukocytes per mm3, will be enrolled in the study.

Participants: Exclusion criteria

Exclusion criteria:

1. Trauma, or relevant underlying illness such as intracranial shunt, previous neurological abnormality (cerebral palsy, Down's syndrome, meningitis)

2. Previous hearing impairment (if known)

3. Immunosuppression, except HIV infection

4. More than one parenteral dose of a pretreatment antimicrobial. Children with oral antimicrobials are included, this information being marked in the FOLLOW-UP sheet.

5. Active tuberculosis (if tuberculotic meningitis is diagnosed during trial, it will be included in intention-to-treat (ITT) analysis)

6. Known hepatic disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Pediatrico David Bernardino	Luanda		Angola

Sponsors and Collaborators

• University of Helsinki
• Foundation for Paediatric Research, Finland

Investigators

• Study Director: Heikki O Peltola, MD, PhD, Childrens Hospital of Helsinki University Central Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 21, 2012

More Information

Publications

• Pelkonen T, Roine I, Cruzeiro ML, Pitkäranta A, Kataja M, Peltola H. Slow initial β-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial. Lancet Infect Dis. 2011 Aug;11(8):613-21. doi: 10.1016/S1473-3099(11)70055-X. Epub 2011 May 5.

• Responsible Party: Heikki Peltola, MD, PhD, Profesor, University of Helsinki
• ClinicalTrials.gov Identifier: NCT01540838
• Other Study ID Numbers: INFU/PARA-BOLU/PLACE
• First Posted: Feb 29, 2012
• Last Update Posted: Sep 24, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Heikki Peltola, MD, PhD, Profesor, University of Helsinki: Bacterial meningitis; infusion; bolus; paracetamol
• Additional relevant MeSH terms: Meningitis, Bacterial; Meningitis; Acetaminophen

Study Results

Participant Flow

Recruitment Details	1128 patients were assessed for eligibility at the Hospital´s Emergency Service from Jan 2012 to Jan 2017. 753 were excluded and 375 enrolled and randomized.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Period Title: Overall Study
STARTED	188	187
COMPLETED	166	164
NOT COMPLETED	22	23

Baseline Characteristics

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo	Total
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.	Total of all reporting groups
Overall Participants	188	187	375
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	43.6 (42.0)	45.7 (43.8)	44.6 (42.9)
Sex: Female, Male (Count of Participants)
Female	87 46.3%	71 38%	158 42.1%
Male	101 53.7%	116 62%	217 57.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	0 0%	0 0%	0 0%
Unknown or Not Reported	188 100%	187 100%	375 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	179 95.2%	178 95.2%	357 95.2%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	9 4.8%	9 4.8%	18 4.8%
Region of Enrollment (Count of Participants)
Angola	188 100%	187 100%	375 100%
Weight-for-age, Z-score (Z-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z-score]	-1.179 (1.376)	-1.239 (1.426)	-1.209 (1.400)

Outcome Measures

1. Primary Outcome

Title	Day 7 Mortality
Description	All patients who had received at least one dose of treatment and were dead on day 7 from the institution of treatment on day 1.
Time Frame	On day 7 from the institution of treatment

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of treatment.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	187	186
Count of Participants [Participants]	61 32.4%	64 34.2%

2. Secondary Outcome

Title	All Deaths During Hospital Stay
Description	All patients who had received at least one dose of treatment and died during the hospital stay.
Time Frame	The outcome was assessed each day until the patient was discharged from the hospital. The longest hospital stay was 84 days, while the last death occurred 39 days after treatment initiation.

Outcome Measure Data

Analysis Population Description

All patients who had received at least one dose of treatment.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	187	186
Count of Participants [Participants]	71 37.8%	75 40.1%

3. Secondary Outcome

Title	Status on the Modified Glasgow Outcome Scale
Description	Scores on the modified Glasgow Outcome Scale which range from a maximum of 5 (best) to a minimum of 1 (worst) points. The Glasgow Outcome Scale categorizes the outcome after brain injury into five categories, based on the level and severeness of disability. As hearing impairment is one of the most common sequelae of bacterial meningitis, an assessment of hearing should be included when estimating the grade of disability. Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately.
Time Frame	Examined at discharge from hospital, except for hearing evaluations which were performed at earliest seven days since the institution of treatment, during the hospital stay. The longest hospital stay was 84 days.

Outcome Measure Data

Analysis Population Description

We were finally able to perform post-treatment audiological examinations in solely 37 participants, of whom one lacked information on the neurological outcome. Thus, the Glasgow Outcome Scale score could be estimated for 36 participants.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	19	17
Median (Inter-Quartile Range) [score on a scale]	5	5

4. Secondary Outcome

Title	Death or Any Neurological Sequelae on Day 7
Description	Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.
Time Frame	Examined on day 7 since institution of treatment.

Outcome Measure Data

Analysis Population Description

All patients who had received at least one dose of treatment, and from whom the information on any neurological sequelae was available on day 7.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	166	168
Count of Participants [Participants]	96 51.1%	86 46%

5. Secondary Outcome

Title	A Change in Hearing Threshold Compared to the First Test Result
Description	Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. The better ear's hearing threshold, obtained on admission or shortly thereafter, was compared with the better ear's hearing threshold obtained at earliest after one week of treatment.
Time Frame	Hearing thresholds obtained during any of the first three days after hospital admission were compared with hearing thresholds obtained on day seven or later, during the hospital stay. The longest hospital stay was 84 days.

Outcome Measure Data

Analysis Population Description

We were finally able to perform post-treatment audiological examinations in solely 37 participants, and 10 of these lacked primary audiological examinations. Thus, this outcome is reported for 27 participants.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	13	14
Median (Inter-Quartile Range) [dB]	0	0

6. Secondary Outcome

Title	Death or Severe Neurological Sequelae on Day 7
Description	Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation
Time Frame	Examined on day 7 since institution of treatment

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of treatment, and of whom information on severe neurological sequelae was available on day 7.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	172	173
Count of Participants [Participants]	80 42.6%	75 40.1%

7. Secondary Outcome

Title	Number of Participants With Deafness
Description	Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. Deafness was defined as a hearing threshold >80 dB in the better ear.
Time Frame	This outcome includes hearing thresholds determined at earliest seven days after the institution of treatment, during the hospital stay. The longest hospital stay was 84 days.

Outcome Measure Data

Analysis Population Description

We were finally able to perform post-treatment audiological examinations in solely 37 participants.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	20	17
Count of Participants [Participants]	3 1.6%	1 0.5%

8. Secondary Outcome

Title	Death or Any Neurological Sequelae at Discharge From Hospital.
Description	Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.
Time Frame	Examined at discharge from hospital. The longest hospital stay was 84 days.

Outcome Measure Data

Analysis Population Description

All patients who hade received at least one dose of treatment, and of whom information on any neurological sequelae was available at discharge from hospital.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	181	179
Count of Participants [Participants]	104 55.3%	89 47.6%

9. Secondary Outcome

Title	Death or Severe Neurological Sequelae at Discharge
Description	Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation
Time Frame	Examined at discharge from hospital. The longest hospital stay was 84 days.

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of treatment, and of whom information on severe neurological sequelae was available at discharge from hospital.

Arm/Group Title	Infusion With Paracetamol	Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.	Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
Measure Participants	186	183
Count of Participants [Participants]	90 47.9%	85 45.5%

Adverse Events

Time Frame	During the patient´s hospital stay of at least 7 days until discharge. The longest hospital stay was 84 days.
Adverse Event Reporting Description	No specific events or findings, a part from the follow up-data detailed in the protocol, were considered as potential adverse events to be registered because both death, serious sequelae, and/or prolonged hospital stay, given as examples of severe adverse events, are part of the possible course of childhood bacterial meningitis, as such. Deaths and other follow-up data were assessed by attending physician.
Arm/Group Title	Infusion With Paracetamol		Bolus With Placebo
Arm/Group Description	Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) Infusion with paracetamol: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.		Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol Bolus without paracetamol: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
All Cause Mortality
	Infusion With Paracetamol		Bolus With Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/188 (38.3%)		76/187 (40.6%)
Serious Adverse Events
	Infusion With Paracetamol		Bolus With Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/188 (0%)		0/187 (0%)
Nervous system disorders
Any adverse events	0/188 (0%)	0	0/187 (0%)	0
Other (Not Including Serious) Adverse Events
	Infusion With Paracetamol		Bolus With Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/188 (0%)		0/187 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.