Intraventricular antibiotics for bacterial meningitis in neonates

Shah S, Ohlsson A, Shah V

 

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 22/08/2007
Date of last substantive update: 17/06/2004
Date of last minor update: 04/07/2007
Date next stage expected 04/07/2009
Protocol first published: Issue 4, 2003
Review first published: Issue 4, 2004

Contact reviewer

Dr Sachin S Shah, MBBS, MD, DM
Director
Neonatal and Pediatric Intensive Care Services
Aditya Birla Memorial Hospital
Office no. 2, Arihant Building
39/32 Karve Road
Pune
INDIA
411004
Telephone 1: 91 20 30717644
Facsimile: 91 20 27277003
E-mail: sshahdoc@hotmail.com
Secondary address:
39/32 Karve Road
1st Floor, Arihant Building
Pune INDIA
411004
Telephone: 91 20 25442244

Contribution of reviewers

All review authors contributed to all stages of the protocol and the full review. The update of the review was conducted by Arne Ohlsson and Vibhuti Shah.

Internal sources of support

Department of Paediatrics, Mount Sinai Hospital, Toronto, Ontario, CANADA

External sources of support

None

What's new

This review updates the review "Intraventricular antibiotics for bacterial meningitis in neonates" published in The Cochrane Library, Issue 4, 2004 (Shah 2004).

A repeat search of the literature was conducted on June 21, 2007. No new trials were identified.

The conclusions remain the same.

Dates

Date review re-formatted: / /
Date new studies sought but none found: 04/07/2007
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis


Infection of the membranes and the fluid surrounding the brain (meningitis) and of the fluid filled spaces in the brain (ventriculitis) may be caused by bacteria, especially gram negative bacteria. This type of infection is difficult to eradicate using safe doses of antibiotics given into the blood stream. In theory, intraventricular administration of antibiotics (administration of antibiotics into the fluid filled spaces in the centre of the brain) would produce higher antibiotic concentrations in the fluid in the brain than intravenous administration alone, and eliminate the bacteria more quickly. However, taps of the fluid filled spaces may cause harm as the needle has to penetrate the brain tissue.

Only one trial was identified. In this trial enrolling infants with gram negative meningitis and ventriculitis, the use of intraventricular antibiotics in addition to intravenous antibiotics resulted in a 3 fold increased risk for mortality compared to standard treatment with intravenous antibiotics alone. Based on this result, intraventricular antibiotics should be avoided. Further trials comparing these interventions are not justified in newborn infants.

Abstract



Background


Neonatal meningitis may be caused by bacteria, especially gram-negative bacteria, which are difficult to eradicate from the cerebrospinal fluid (CSF) using safe doses of antibiotics. In theory, intraventricular administration of antibiotics would produce higher antibiotic concentrations in the CSF than intravenous administration alone, and eliminate the bacteria more quickly. However, ventricular taps may cause harm.

Objectives


To assess the effectiveness and safety of intraventricular antibiotics (with or without intravenous antibiotics) in neonates with meningitis (with or without ventriculitis) as compared to treatment with intravenous antibiotics alone.

Search strategy


MEDLINE, EMBASE, CINAHL, The Cochrane Library, Issue 2, 2007, and Science Citation Index were searched in June 2007. The Oxford Database of Perinatal Trials were searched in June 2004. Pediatric Research (abstracts of proceedings) were searched (1990 - April 2007) as were reference lists of identified trials and personal files. No language restrictions were applied.

Selection criteria


Selection criteria for study inclusion were: randomized or quasi-randomized controlled trials in which intraventricular antibiotics with or without intravenous antibiotics were compared with intravenous antibiotics alone in neonates (< 28 days old) with meningitis. One of the following outcomes was required to be reported: mortality during initial hospitalization, neonatal and/or infant mortality, neurodevelopmental outcome, duration of hospitalization, duration of culture positivity of CSF and side effects.

Data collection & analysis


All review authors abstracted information for outcomes reported and one review author checked for discrepancies and entered data into RevMan 4.2. Relative risk (RR), risk difference (RD), number needed to treat (NNT) or number needed to harm (NNH), and mean difference (MD), using the fixed effects model are reported with 95% confidence intervals (CI). The fixed effect model was used for meta-analysis.

Main results


The updated search in June 2007 did not identify any new trials. One study was included in the review. This study assessed the effect of intraventricular gentamicin in a mixed population of neonates (69%) and older infants (31%) with gram negative meningitis and ventriculitis. Mortality was statistically significantly higher in the group that received intraventricular gentamicin in addition to intravenous antibiotics compared to the group receiving intravenous antibiotics alone [RR 3.43 (95% CI, 1.09, 10.74; RD 0.30 (95% CI, 0.08, 0.53); NNH was 3 (95% CI; 2 ,13)]. Duration of CSF culture positivity did not differ significantly (MD -1.20 days (95% CI, -2.67, 0.27).

Reviewers' conclusions


In one trial, enrolling infants with gram negative meningitis and ventriculitis, the use of intraventricular antibiotics in addition to intravenous antibiotics resulted in a three-fold increased RR for mortality compared to standard treatment with intravenous antibiotics alone. Based on this result, intraventricular antibiotics as tested in this trial should be avoided. Further trials comparing these interventions are not justified in this population.

Background


Bacterial meningitis is more common in the first month of life than at any other age (Pong 1999). The epidemiology of meningitis in the neonatal period is similar to that of neonatal sepsis. Meningitis can occur as a part of sepsis in both the early and late-onset time periods or as focal infection as late-onset disease (Klein 2000; Pong 1999). The incidence of neonatal bacterial meningitis ranges from 0.25 to 1 per 1000 live births (Bell 1989; Hristeva 1993). Meningitis occurs in approximately 25% of neonates with bacteremia (Klein 2000). The risk factors for meningitis include preterm birth, maternal chorioamnionitis, prolonged pre-labour rupture of fetal membranes and presence of a foreign body such as a cerebrospinal fluid (CSF) shunt (Klein 2000; Ronan 1995).

Group B β-hemolytic streptococci (GBS), gram negative enteric bacteria, and Listeria monocytogenes are the most common agents causing meningitis (Pong 1999). Infection with gram negative bacilli accounts for 30 - 40% of cases of meningitis (Dawson 1999), with Escherichia coli (E. Coli) being the most common organism isolated (50% of all gram negative isolates) (Anderson 1990; Dawson 1999; Unhanand 1993) followed by klebsiella species (Klein 2000). Other organisms that have been implicated to cause meningitis include enterobacter, citrobacter and serratia species (Polin 2001). Meningitis with organisms such as coagulase negative staphylococcus and pseudomonas species (Polin 2001) is more common in neonates requiring prolonged hospitalization, need for central venous catheters, parenteral nutrition and ventilatory support.

Prior to the availability of antibiotics, bacterial meningitis was a uniformly fatal disease (Flexner 1913; Scheld 1984). The development of modern methods of intensive care and newer antibiotics resulted in decline in mortality to 10 - 25% in infancy (Dawson 1999; Harvey 1999; Heath 2003). However, the incidence of neurological morbidity in infants who survive bacterial meningitis is high, ranging from 20% - 80%, and is somewhat dependent on the infecting organism (Harvey 1999; Heath 2003; Klinger 2000). Acute complications of meningitis include death, seizures, ventriculitis, hydrocephalus, subdural effusion and brain abscess (Baumgartner 1983; Hristeva 1993). The disease is often more severe with gram negative bacteria than gram positive bacteria, with higher rates of both mortality and morbidity (Franco 1992). Gram negative meningitis results in prolonged duration of CSF bacterial culture positivity compared to group B streptococcus. A delay in achieving CSF sterilization has been shown to be associated with increased neurological sequelae (McCracken 1972; Unhanand 1993). Long term sequelae amongst survivors of meningitis include hydrocephalus, developmental delay, cerebral palsy, seizures requiring anticonvulsant therapy, decreased visual acuity and hearing loss (Baumgartner 1983; Hristeva 1993).

For these reasons, antibiotic therapy for meningitis should be aggressive. The doses used must achieve a bactericidal concentration of antibiotic in the cerebrospinal fluid (CSF). The standard therapy for neonatal meningitis is intravenous administration of antibiotics. Efficient elimination of bacteria depends not only on the ability of an antibiotic to enter the CSF, but also on the relationship between the concentration of antibiotic in the CSF and the minimal bactericidal concentration (MBC) for the infecting pathogen. Therefore, while gentamicin can enter CSF relatively readily (CSF/serum concentration 20 - 25%), the concentrations achieved in CSF are close to the MBC only for susceptible organisms (McCracken 1982; Polin 2001). In contrast, β-lactam antibiotics such as penicillins or cephalosporins enter CSF less readily, but because larger doses can be used without toxicity, the concentrations achieved are far higher than the MBC (Polin 2001). Since CSF drug concentrations can lag behind serum drug levels, a single measurement may underestimate the true ability of a drug to enter the CSF. The more reliable estimate is the area under concentration curve, but that requires multiple CSF samples and cannot be routinely done in humans (Polin 2001).

The initial choice of intravenous antibiotics for neonates with suspected meningitis must cover both gram positive and gram negative organisms (Quagliarello 1997). Therefore, empiric therapy generally includes ampicillin in addition to either an aminoglycoside or a third generation cephalosporin. Once a pathogen has been isolated, antibiotic therapy for bacterial meningitis can be tailored to the pathogen.

In theory, the intraventricular route of administration of antibiotics would achieve higher antibiotic concentrations in the CSF and eliminate the bacteria more quickly. In a prospective study of 16 infants with neonatal meningitis, Lee and co-workers (Lee 1977) used a combination of systemic and intraventricular antibiotics. Fifteen infants survived the infection and, of these infants, seven were normal on follow-up. There were no acute adverse reactions after the use of intraventricular antibiotics. A retrospective review of gram negative meningitis in neonates demonstrated that the mortality was lower after intraventricular plus systemic antibiotic therapy than after systemic antibiotic therapy alone (Wright 1981). The authors suggested that if careful attention is given to the pharmacokinetics of intraventricular therapy, this route may be a valuable adjunct to therapy for gram negative meningitis. Techniques used for intraventricular drug administration in these trials included repeated ventricular taps, open or closed implanted catheter, or use of Omaya or Rickham reservoir. Intraventricular antibiotics have also been used in children with cerebrospinal fluid shunt infection with variable results (James 1980; Stamos 1993) and controversy exists as to the best treatment of shunt infections. Several therapeutic modalities are currently used for the treatment of shunt infections including: 1) intravenous antibiotics with/without intra shunt antibiotics with shunt removal and external ventricular drain or ventricular taps; 2) intravenous antibiotics with/without intra shunt antibiotics with shunt removal and immediate replacement; and 3) intravenous antibiotics with/without intra shunt antibiotics without removal of the infected shunt (James 1980; Whitehead 2001)

However, a ventricular tap for the administration of antibiotics is an invasive procedure that is associated with its own risks. Repeated needle aspirations of ventricular fluid have been associated with development of porencephalic cysts (Salmon 1967). In healthy adult rabbits, Watanabe and co-workers were consistently able to produce widespread axonal degeneration, myelin swelling and glia-cell necrosis after intracisternal inoculation of gentamicin (Watanabe 1978).

Studies have been conducted in neonates with bacterial meningitis with the hypothesis that larger concentrations of drug resulting from direct inoculation into the CSF space would sterilize cultures more rapidly and improve outcome from the disease. This systematic review evaluates the evidence from those trials.

Objectives


Primary objective:
To determine the effectiveness and safety of intraventricular antibiotics (with or without intravenous antibiotics) in neonates with meningitis (with or without ventriculitis) as compared to conventional treatment with intravenous antibiotics alone.

To assess the effectiveness and safety of intraventricular antibiotics, the following separate comparisons were planned:

Secondary objectives:
To determine in subgroup analyses the effectiveness and safety of intraventricular antibiotics in relation to the following criteria:


Criteria for considering studies for this review



Types of studies


Randomized or quasi-randomized controlled trials.

Types of participants


Term or preterm (< 37 weeks gestational age) infants in the neonatal period (< 28 days) with bacterial meningitis with or without ventriculitis.
The criteria for diagnosis of bacterial meningitis should include the following:
1. Positive CSF culture and/or positive gram stain

The criteria for diagnosis of ventriculitis should include one of the following:
1. Positive ventricular fluid culture
2. Leucocytosis (> 50 cells/cmm) with/without organisms identified on gram staining

Types of interventions


The intervention should be intraventricular administration of any antibiotic (of any duration) with or without intravenous antibiotic treatment compared with intravenous antibiotic treatment alone.
The antibiotic used for intraventricular administration may/may not be the one used for intravenous therapy.

Types of outcome measures


Primary outcome

Secondary outcomes:


Search strategy for identification of studies


See: Cochrane Neonatal Review Group search strategy.

MEDLINE database (1966 - June 2007) was searched using MeSH terms: "infant, newborn" AND "meningitis" AND "intraventricular" AND "antibiotics" AND (random allocation OR controlled trial OR randomized controlled trial). The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), EMBASE (1980 - June 2007) and CINAHL (1982 - June 2007), and abstracts (American Pediatric Society and European Society for Pediatric Research annual meetings) published in Pediatric Research (1990 - April 2007) were searched either manually or electronically in the PAS Abstract Archive (2000 - 2007). The reference lists of identified trials were searched to identify potential articles for inclusion. Science Citation Index was searched on the reference to the only trial found (McCracken 1980). The Oxford Database of Perinatal Trials was searched for the initial review. Unpublished data were not sought, but authors of published trials were to be contacted to clarify or provide additional information. No language restrictions were applied. The retrieved articles were screened by the three review authors to identify articles eligible for inclusion in this review.

Methods of the review


The standardized review methods of the Cochrane Neonatal Review Group (CNRG) were used to assess the methodological quality of studies.

All abstracts and published full reports identified as potentially relevant by the literature were assessed for inclusion in the review by the authors. Each author extracted data separately using pre-designed data abstraction forms and then compared the results. One review author entered the data into RevMan and the other review authors cross checked the printout against their own data abstraction forms and errors were corrected by consensus.
For the studies identified as abstracts, primary authors were to be contacted to ascertain whether a full publication is available if the full paper was not identified in an electronic data base. Information from the primary author of the identified trial (McCracken 1980) was contacted for additional information.

Quality assessments of the retrieved articles were conducted by the review authors, who were not blinded to authors, institution or journal of publication. The quality of included trials was evaluated independently by the review authors, using the following criteria:
Blinding of randomization?
Blinding of intervention?
Blinding of outcome measure assessment?
Completeness of follow up?

There are three potential answers to these questions - yes, can't tell, no

The statistical analyses followed the recommendations of the Cochrane Neonatal Review Group and were performed using the RevMan 4.2 software. The estimates of treatment effects included relative risk (RR), risk difference (RD), number needed to treat (NNT) or number needed to harm (NNH) for dichotomous outcomes, and weighted mean difference (WMD) [or mean difference (MD) if only one trial was included] for continuous outcomes. All estimates of treatment effects are reported with 95% confidence intervals (CI). A fixed effects model was to be used for meta-analyses. Heterogeneity tests (including the I2 test) were to be performed to assess the appropriateness of pooling the data. Planned subgroup analyses were to be performed according to the criteria listed under objectives. No sensitivity analyses were planned a priori, but could be conducted depending on the results.

Description of studies


The literature search did not identify any study that strictly met all of the inclusion criteria either in June 2004 or in the updated search in June 2007. However, one randomized controlled trial conducted in both neonates and infants was identified (McCracken 1980). Outcomes specific to the different age groups could not be abstracted. The primary author was contacted and asked whether data for the infants < 28 days could be provided. He responded that he no longer had the original data from that study. We chose to deviate from our protocol and included this study in this systematic review as 69 % of the randomized infants with ventriculitis were less than 30 days old at the time of enrollment. The study was conducted in 20 institutions in the US and Latin America more than 25 years ago. The rationale for enrolling only infants with meningitis caused by gram negative bacteria was based on the high mortality in this population and the longer duration of CSF positivity in meningitis caused by gram negative bacteria compared to gram positive bacteria. Higher concentrations of gentamicin for longer duration in intraventricular fluid following intraventricular injection had previously been found in adults, justifying this trial in infants. Eighty-seven infants were considered for enrollment in the study but 16 were found unacceptable (See Table - Characteristics of included studies for details). The remaining 71 infants had ventricular taps and lumbar punctures. Nineteen did not have ventriculitis and these infants were assigned to receive systemic antibiotics plus lumbar intrathecal gentamicin or systemic antibiotics only. The latter stratum was not included in this review as neither group received intraventricular antibiotics. Fifty two infants with meningitis (caused by gram negative enteric bacilli) and ventriculitis (diagnosed by >/= 50 white cells/ml ventricular fluid with or without gram negative rods on stained smear or culture of ventricular fluid) were randomly allocated to receive either intraventricular antibiotics and intravenous antibiotics or intravenous antibiotics alone. Only these 52 infants are included in this review. The most commonly isolated bacteria were E coli (38.5%), klebsiella-enterobacter and citrobacter (28.8%), and Salmonella (19.2%). Other organisms were found in 13.5% of the infants. Outcomes that were reported included mortality during hospital stay, days of positive CSF cultures (obtained from intraventricular and or lumbar CSF samples) and morbidity on follow-up examinations.

Methodological quality of included studies


In the included study (McCracken 1980) the allocation of the study subjects to the two interventions was concealed. The researchers/health care providers could not be blinded to the interventions. It is unclear whether the outcome assessments, specifically the long-term assessments, were performed blinded to group assignment. Survivors were scheduled for follow-up evaluations six and 12 months after illness and yearly thereafter. Complete physical, neurological, and Denver developmental examinations were to be done at each visit. The Cattell infant intelligence and Gessell fine and gross motor developmental tests were administered to some infants aged 12 months or more. The authors do not state the age of the infants/children at the time of their follow-up and the number of children who underwent which exam/test. No sample-size calculation or any pre-determined stopping rules were reported. The study was terminated early because of the higher mortality rate in the intraventricular-therapy group.

Results



INTRAVENTRICULAR PLUS INTRAVENOUS ANTIBIOTICS VERSUS INTRAVENTRICULAR ANTIBIOTICS ALONE (Comparison 01):

One study (McCracken 1980) was included for this comparison.

Primary outcome:

All Cause Mortality During the Hospital Stay (Outcome 01.01):

The mortality was statistically significantly higher in the group that received intraventricular antibiotics and intravenous antibiotics compared to the group that received intravenous antibiotics only. The RR (relative risk) was 3.43 (95% CI 1.09, 10.74); RD (risk difference) was 0.30 (95% CI 0.08, 0.53) and NNH (number needed to harm) was 3 (95% CI 2, 13). In a secondary publication (Mustafa et al 1989), the same group reported increased endotoxin and interleukin-1β concentrations in cerebrospinal fluid of infants with coliform meningitis and ventriculitis associated with intraventricular gentamicin therapy. This subgroup of 21 patients, of which 10 received intraventricular and intravenous antibiotics and 11 received intravenous antibiotics alone, were included in the original trial (McCracken 1980). The authors proposed that intraventricular gentamicin may cause release of endotoxin from gram negative bacilli in ventricular cerebrospinal fluid, resulting in increased interleukin-1β concentrations and inflammation, which could have contributed to the poor outcome in these patients.

Secondary outcomes:

Neonatal Mortality (death during the first 28 days of life):

Data for this outcome could not be abstracted.

Infant Mortality (death during the first year of life):

Data for this outcome could not be abstracted. Most deaths occurred within 14 days after the therapy was started. One infant/child died 36 days after the therapy was started from aspiration pneumonia and one from recurrence of meningitis 199 days following enrollment in the study. These deaths could have occurred beyond one year of age.

Neurodevelopmental Outcome: (neurodevelopmental outcome assessed by a standardized and validated assessment tool and/or a child developmental specialist) at any age (outcome data to be grouped at 12, 18, 24 months if available):

It is unclear how old the infants were when assessed for long-term morbidity. We contacted the primary author, but the research team no longer had the original data to make clarifications.

Duration of Hospitalization (total length of hospitalization from birth to discharge home or death):

This outcome was not reported.

Duration of Culture Positivity of CSF (Outcome 01.02):

There was no statistically significant difference in the days of positive CSF cultures (ascertained by ventricular and/or lumbar CSF specimens); mean difference -1.20 days (95% CI -2.67, 0.27) with a trend favouring the intraventricular and intravenous antibiotics group compared to the intravenous antibiotics only group.

Antimicrobial Side-Effects (diarrhea, fungal infection, anaphylaxis etc):

None of these potential side effects were reported, but the authors speculate that the increased case-fatality rate in the intraventricular antibiotics group could be related to the procedure or to a direct toxic effect of gentamicin. See also information under "All cause mortality during the hospital stay" above.

INTRAVENTRICULAR ANTIBIOTICS ALONE VERSUS INTRAVENOUS ANTIBIOTICS ALONE
INFANTS WITH OR WITHOUT A CSF SHUNT

No eligible studies were found which allowed us to undertake either of these planned comparisons.

Planned Subgroup Analyses:

None of the planned subgroup analyses (by gestational age or birth weight classes, presence or absence of ventriculitis, type of organism, or antibiotic used) could be conducted, because of lack of eligible data.

Discussion


In this review we could compare intraventricular antibiotics and intravenous antibiotics with intravenous antibiotics alone only in infants with proven ventriculitis/meningitis due to gram negative organisms. This is likely to be the population that most justifies the intervention that was studied. In theory, the intraventricular route of administration of antibiotics would achieve higher antibiotic concentrations in the CSF and eliminate the bacteria more quickly.

Only one randomized or quasi-randomized trial related to this topic could be identified. The updated literature search in June 2007 did not identify any additional studies for inclusion. The included study did not strictly fulfill all our selection criteria as the study included both neonates (69% of the infants were < 29 days old) and older infants (31%). As the majority of infants enrolled were neonates we considered it appropriate to report on the results of this study. The randomized controlled study design included concealed allocation to the two interventions, thus avoiding a major threat to validity. It is unclear if the outcomes were assessed blinded to group. This is more of a concern regarding the long-term follow-up assessments among survivors than all cause mortality, which is an undisputable outcome. The authors do not provide enough information to draw any conclusion regarding long-term developmental outcomes (age at assessment, incidence and degree of motor, cognitive and sensory impairments). No imaging techniques were applied to ascertain any damage caused by the intraventricular taps.

There was no statistically significant reduction in the duration of culture positivity of CSF, the major underlying rationale for intraventricular antibiotics in infants with meningitis/ventriculitis.

With the markedly increased mortality in the group receiving intraventricular plus intravenous antibiotics compared to the group receiving intravenous antibiotics group alone, further trials in neonates are not justified. The increased mortality could be related to the procedure itself or to toxicity of the intraventricularly administered gentamicin (McCracken 1980). The increased mortality in the intraventricular antibiotics group is the likely reason why no further trials have been conducted.

Reviewers' conclusions



Implications for practice


In infants with meningitis and ventriculitis, intraventricular antibiotics in combination with intravenous antibiotics resulted in a three-fold increased relative risk for mortality compared to standard treatment with intravenous antibiotics alone and should be avoided. These conclusions are based on one trial which enrolled infants with gram negative meningitis and ventriculitis.

Implications for research


Further trials comparing intraventricular and intravenous antibiotics to intravenous antibiotics alone are not justified in this population.

Acknowledgements


We thank Dr. George H. McCracken Jr for answering questions related to the included trial.

Potential conflict of interest


None

Characteristics of included studies

StudyMethodsParticipantsInterventionsOutcomesNotesAllocation concealment
McCracken 1980Multicentre (20 institutions in the US and Latin America) randomized controlled trial
Recruitment dates March, 1976 to December 1979
Blinding of randomization - Yes (sealed numbered envelopes)
Blinding of intervention - No
Blinding of outcome measure assessment - Can't tell
Completeness of follow up - Yes		87 infants were considered for enrollment.
16 infants were found unacceptable for the following reasons: (1) CSF cultures from 6 infants were sterile or yielded non-enteric organisms;
(2) the pathogens from 4 patients were known to be resistant in vitro to ampicillin and gentamicin before enrolment; (3)
2 infants died before treatment was started; (4)
2 infants' physicians would not allow their patients to be enrolled; (5) in
1 infant ventriculitis could not be distinguished from intraventricular haemorrhage; and (6) 1 infant with Down syndrome was excluded because of the difficulty in evaluating neurological and mental status after therapy.
The remaining 71 infants comprised the study population.
52 infants (73%) had meningitis and ventriculitis at the time of enrolment and 19 infants (27%) did not have ventriculitis
16 of the 52 infants with ventriculitis were >/= to 30 days old (31%). Thus 69% of the infants were 29 days or younger (close to the conventional definition of a neonate, i.e. < 28 days of age).		Intraventricular antibiotics (n=28).
2.5 mg gentamicin intraventricularly per day for a minimum of 3 days.
No intraventricular antibiotics (n=24).
No intraventricular drug or placebo.
All infants in both groups received systemic antibiotics: for those </= 7 days, ampicillin 50 mg/kg q12h i.v. and gentamicin 2.5 mg/kg q12h i.m. or i.v., for those >7 days, ampicillin 70 mg/kg q8h i.v. and gentamicin 2.5 mg/kg q8h i.m. or i.v.		Mortality
Days positive CSF cultures
Long term follow-up		19 infants had meningitis without ventriculitis. 9 of these were assigned to lumbar intrathecal gentamicin plus systemic antibiotics, and 10 to systemic antibiotics only. These two groups were not included in this review because intraventricular antibiotics were not tested in these infants.A

References to studies

References to included studies

McCracken 1980 {published data only}

* McCracken GH, Mize SG, Threlkeld N. Intraventricular gentamicin therapy in Gram-negative bacillary meningitis of infancy. Lancet 1980;1:787-91.

Mustafa MM, Mertsola J, Ramilo O, Saez-Llorens X, Risser RC, McCracken GH. Increased endotoxin and interleukin1-beta concentrations in cerebrospinal fluid of infants with coliform meningitis and ventriculitis associated with intraventricular gentamicin therapy. The Journal of Infectious Diseases 1989;160:891-5.

* indicates the primary reference for the study

Other references

Additional references

Anderson 1990

Anderson SG, Gilbert GL. Neonatal gram negative meningitis: a 10-year review, with reference to outcome and relapse of infection. Journal of Paediatrics and Child Health 1990;26:212-16.

Baumgartner 1983

Baumgartner ET, Augustine RA, Steele RW. Bacterial meningitis in older neonates. American Journal of Diseases of Children 1983;137:1052-4.

Bell 1989

Bell AH, Brown D, Halliday HL, McClure G, McReid M. Meningitis in the newborn - a 14 year review. Archives of Disease in Childhood 1989;64:873-4.

Chotpitayasunondh 94

Chotpitayasunondh T. Bacterial meningitis in children: etiology and clinical features, an 11 year review of 618 cases. Southeast Asian Journal of Tropical Medicine and Public Health 1994;25:107-15.

Dawson 1999

Dawson KG, Emerson JC, Burns JL. Fifteen years of experience with bacterial meningitis. Pediatric Infectious Disease Journal 1999;18:816-22.

Flexner 1913

Flexner S. The results of serum treatment in thirteen hundred cases of epidemic meningitis. Journal of Experimental Medicine 1913;17:553-76.

Franco 1992

Franco SM, Cornelius VE, Andrews BF. Long-term outcome of neonatal meningitis. American Journal of Diseases of Children 1992;146:567-71.

Harvey 1999

Harvey D, Holt DE, Bedford H. Bacterial meningitis in the newborn: a prospective study of mortality and morbidity. Seminars in Perinatology 1999;23:218-25.

Heath 2003

Heath PT, Yusoff NK, Baker CJ. Neonatal meningitis. Archives of Disease in Childhood Fetal Neonatal Edition 2003;88:F173-8.

Hristeva 1993

Hristeva L, Booy R, Bowler I, Wilkinson AR. Prospective surveillance of neonatal meningitis. Archives of Disease in Childhood 1993;69:14-8.

James 1980

James HE, Wlash JW, Wilson HD, Connor JD, Bean JR, Tibbs PA. Prospective randomized study of therapy in cerebrospinal fluid shunt infection. Neurosurgery 1980;7:459-63.

Klein 2000

Klein JO. Bacterial meningitis and sepsis. In: Remington JS, Klein JO (eds) Infectious diseases of the fetus and newborn infant. Philadelphia: WB Saunders, 2000:943-98.

Klinger 2000

Klinger G, Chin CN, Beyene J, Perlman M. Predicting the outcome of neonatal bacterial meningitis. Pediatrics 2000;106:477-82.

Klugman 1995

Klugman DP, Dagan R. Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Meropenem Meningitis Study Group. Antimicrobial Agents and Chemotherapy 1995;39:1140-6.

Lee 1977

Lee EL, Robinson MJ, Thong ML, Puthucheary SD, Ong TH, Ng KK. Intraventricular chemotherapy in neonatal meningitis. Journal of Pediatrics 1977;91:991-5.

McCracken 1972

McCracken GH. The rate of bacteriologic response to antimicrobial therapy in neonatal meningitis. American Journal of Diseases of Children 1972;123:547-53.

McCracken 1982

McCracken GH, Nelson JD, Grimm L. Pharmacokinetics and bacteriological efficacy of cefoperazone, ceftriaxone, and moxalactam in experimental Streptococcus pneumoniae and Haemophilus influenzae meningitis. Antimicrobial Agents and Chemotherapy 1982;21:262-7.

Moreno 1994

Moreno MT, Vargas S, Poveda R, Saez-Llorens X. Neonatal sepsis and meningitis in a developing Latin American country. Pediatric Infectious Disease Journal 1994;13:516-20.

Polin 2001

Polin RA, Harris MC. Neonatal bacterial meningitis. Seminars in Neonatology 2001;6:157-72.

Pong 1999

Pong A, Bradley JS. Bacterial meningitis and the newborn infant. Infectious Disease Clinics of North America 1999;13:711-33.

Quagliarello 1997

Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. New England Journal of Medicine 1997;336:708-16.

Ronan 1995

Ronan A, Hogg GG, Klug GL. Cerebrospinal fluid shunt infections in children. Pediatric Infectious Disease Journal 1995;14:782-6.

Salmon 1967

Salmon JH. Puncture porencephaly. Pathogenesis and prevention. American Journal of Diseases of Children 1967;114:72-9.

Scheld 1984

Scheld WM, Mandell GL. Landmark perspective. Sulfonamides and meningitis. JAMA 1984;251:791-4.

Stamos 1993

Stamos JK, Kaufman BA, Yogev R. Ventriculoperitoneal shunt infections with gram-negative bacteria. Neurosurgery 1993;33:858-62.

Tessin 1990

Tessin I, Trollfors B, Thiringer K. Incidence and etiology of neonatal septicaemia and meningitis in Western Sweden 1975-1986. Acta Paediatrica Scandinavica 1990;79:1023-30.

Unhanand 1993

Unhanand M, Mustafa MM, McCracken GH, Nelson JD. Gram-negative enteric bacillary meningitis: a twenty-one-year experience. Journal of Pediatrics 1993;122:15-21.

Watanabe 1978

Watanabe I, Hodges GR, Dworzack DL, Kepes JJ, Duensing GF. Neurotoxicity of intrathecal gentamicin: a case report and experimental study. Annals of Neurology 1978;4:564-72.

Whitehead 2001

Whitehead WE, Kestle JR. The treatment of cerebrospinal fluid shunts. Results from a practice survey of the American Society of Pediatric Neurosurgeons. Pediatric Neurosurgery 2001;35:205-10.

Wright 1981

Wright PF, Kaiser AB, Bowman CM, McKee KT Jr, Trujillo H, McGee ZA. The pharmacokinetics and efficacy of an aminoglycoside administered into the cerebral ventricles in neonates: implications for further evaluation of this route of therapy in meningitis. Journal of Infectious Diseases 1981;143:141-7.

Other published versions of this review

Shah 2004

Shah S, Ohlsson A, Shah V. Intraventricular antibiotics for bacterial meningitis in neonates. Cochrane Database of Systematic Reviews 2004, Issue 4.

Comparisons and data

01 Intraventricular antibiotics for meningitis in infants receiving intravenous antibiotics

01.01 All cause mortality during hospital stay

01.02 Duration of culture positivity of CSF (days)


Contact details for co-reviewers

Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca

Dr Vibhuti S Shah
Staff Neonatologist
Department of Paediatrics
Mount Sinai Hospital
Room 775A
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: 416 586 4816
Telephone 2: 416 664 6708
Facsimile: 416 586 8745
E-mail: vshah@mtsinai.on.ca

 
This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.