Schonfeld H, Helwig H (eds): Bacterial Meningitis. Antibiot Chemother. Basel, Karger, 1992, vol 45, pp 226-238
Adverse Outcome of Bacterial Meningitis due to Delayed Sterilization of Cerebrospinal Fluid Marc H. Lebel Department of Pediatrics and Microbiology-Immunology, Sainte-Justine Hospital, University of Montreal, Que., Canada
In the past two decades, there have been many changes in the choice of initial antibiotic therapy for treatment of bacterial meningitis in infants and children. Therapy has evolved from ampicillin alone to a combination of ampicillin plus chloramphenicol due to emergence of 13-lactamaseproducing strains of Haemophilus injluenzae type b. With the availability of newer generation cephalosporins at the beginning of the 1980s, many centers have been using second- and third-generation cephalosporins for meningitis caused by H. injluenzae, Streptococcus pneumoniae, Neisseria meningitidis or gram-negative enteric bacilli. Despite the availability of antimicrobial agents with increased in vitro activity and improvement in supportive care, bacterial meningitis still causes neurologic sequelae in a significant number of survivors [1-5]. This chapter summarizes the recent information on delayed cerebrospinal fluid (CSF) sterilization, how it adversely affects the outcome of patients with meningitis, and the factors involved in the delay of sterilization.
There is no standard definition for delayed CSF sterilization. A small percentage of infants and children with bacterial meningitis will have a CSF culture positive for bacteria on repeat lumbar puncture performed at 18-48 h after initiation of antibiotic treatment. In this article, CSF sterilization will be considered delayed when repeat CSF cultures are positive after 18-36 h of appropriate antibiotic therapy.
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Definition of Delayed CSF Sterilization
Adverse Outcome of Bacterial Meningitis
227
The exact incidence of delayed CSF sterilization is difficult to determine from the literature because of the differences in timing of the followup lumbar punctures after initiation of therapy, dosing schedule of the antibiotics, and culture techniques. The ability to detect persistently positive CSF cultures after initiation of antibiotic therapy will depend on the culture technique used. For antibiotics that produce relatively low CSF bactericidal titers like ampicillin or cefuroxime, routine microbiologic techniques are sufficient. However, for antibiotics that produce high CSF bactericidal titers, like cefotaxime and ceftriaxone, special techniques (i.e., serial dilutions or inactivation of the antibiotic by addition of a cephalosporinase to the CSF sample) are needed. In one study using ceftriaxone, the CSF samples obtained 24 h after start of therapy were cultured with and without a cephalosporinase. All samples cultured in a routine manner (i.e., no cephalosporinase) were sterile, whereas 5% were positive when a cephalosporinase was added. With the newer generation f3-lactam compounds, rates of CSF sterilization from 90 to 100% have been reported when the repeat CSF cultures were done between 15 and 48 h after initiation of therapy [3-18]. Delayed CSF sterilization has been reported in 8-23% of patients treated with ampicillin [19- 23], 6-34% with chloramphenicol [5, 23, 24], 4-16% with cefuroxime [4,9, 10,25,26],2-5% with ceftazidime [11, 12], 0-9% with ceftriaxone [5, 13, 14,26,27]' and 2-7% with cefotaxirne [5, 15,28,29]. In a prospective multicenter trial, Peltola et al. [5] compared chloramphenicol, ampicillin, cefotaxime and ceftriaxone therapy for childhood bacterial meningitis. The CSF sterilization rates of each antibiotic is shown in figure 1. In this study, ceftriaxone appears to be the antimicrobial agent with the fastest sterilization rate. After 12 h of therapy, only 16% of ceftriaxone-treated patients had positive CSF cultures compared to 46% for all other antibiotics combined (p < 0.01) [5]. After 24 h of therapy, ceftriaxone and cefotaxime achieved similar rates of CSF sterilization. The faster CSF sterilization rate obtained with ceftriaxone in the early stages of treatment did not correlate with an improved clinical outcome. However, in other studies neurologic outcome did correlate with sterilization rate after 24 h of therapy [6, 19]. In Peltola's study [5], delayed CSF sterilization occurred significantly more often in the ampicillin plus chloramphenicol treatment group than in the ceftriaxone or cefotaxime treatment group. Three of 3 patients with S. pneumoniae meningitis treated with chloramphenicol had positive CSF cultures after 24 h of treatment. Treatment was extended or modified more frequently in the chloramphenicol group than in the other groups.
Downloaded by: Université de Paris 193.51.85.197 - 1/30/2020 4:24:10 PM
Incidence of Delayed CSF Sterilization
228
Lebel 100.-----------------------------~
Chloramphenicol Amplclliln Cefotaxime
..-. 80 ":!!.
Ceftriaxone
~
en UJ II:
:)
I-
60
...J
--I--------------------- -----
-----l-------~~--"~..
--_._----1---------"Ir--~--""!oiilI~------------·---
:)
0
LL
en
.'.
40
".
0
UJ
>
~
en 0
--
20
............ ~ .
D.
.......
•••••••••••::!
o+-------+-------~------~------~------~------~
Diagnosis
12 hours
24 hours
DURATION OF THERAPY Fig_ 1_ Sterilization of CSF after initiation of antibiotic therapy [adapted from
51-
Newborn In the neonatal period, sterilization of CSF is achieved easily in most patients with meningitis caused by gram-positive organisms. In a review of 16 patients with meningitis caused by Streptococcus agalactiae (group B Streptococcus), Listeria monocytogenes, enterococci and Staphylococcus, only 1 (6%) patient with L. monocytogenes meningitis had persistently positive CSF cultures despite adequate therapy [30]. Delayed CSF sterilization has been described in some infants with group B streptococcal meningitis [31-35]. Tolerance to penicillin might explain some of these cases [31]. Determination of minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) should be done on all meningeal isolates to detect tolerance to penicillin. However, failure to achieve prompt sterilization may be due to an inappropriate dose of an adequate antibiotic or the presence of an unsuspected suppurative focus
Downloaded by: Université de Paris 193.51.85.197 - 1/30/2020 4:24:10 PM
Adverse Outcome due to Delayed CSF Sterilization
Adverse Outcome of Bacterial Meningitis
229
Infants More than Three Months of Age and Children Children with H. injluenzae type b meningitis treated with ampicillin have a 6-fold increased risk of neurologic abnormalities including seizure disorders and cortical blindness at the time of discharge from the hospital if they have a positive CSF culture on repeat spinal tap after 19-36 h of therapy compared with those who have prompt eradication of the CSF pathogen (table 1). At follow-up examinations, patients with delayed CSF sterilization had a 6-fold increase in the incidence of neurological complications [19]. In that study, there were no differences in the demographic and clinical characteristics between the group with delayed or prompt sterilization and no correlation between severity of illness and
Downloaded by: Université de Paris 193.51.85.197 - 1/30/2020 4:24:10 PM
[32]. Despite prompt CSF sterilization in most infants with group B streptococcal meningitis, 20-50% of survivors have long-term sequelae [36, 37]. Delayed CSF sterilization occurs frequently in infants with meningitis caused by gram-negative bacilli [38, 39]. In one study, 59% (13/22) had positive CSF cultures for more 2 days after initiation of antimicrobial therapy [30] . At follow-up examinations 2-3 years after the episode of meningitis, 88% (7/8) of those with delayed CSF sterilization had detectable sequelae. In the First Neonatal Meningitis Collaborative Study, patients who expired (n = 11) had a statistically longer duration of positive CSF cultures (3.5 ± 0.4 vs. 2.0 ± 0.3 days) and days of interleukin-lJ3 concentrations> 200 ngll (3.3 ± 0.5 vs. 1.3 ± 0.3 days) than those that survived and had no sequelae (n = 18), respectively [40, 41]. In another report from the same group, the mean duration of positive CSF culture was 2.8 days in normal survivors versus 5.8 days in survivors with sequelae of Escherichia coli meningitis [42]. In the Third Neonatal Meningitis Cooperative Study Group, moxalactam and ampicillin were compared to amikacin and ampicillin therapy for meningitis caused by gram-negative enteric organisms in 63 infants [38]. The mean duration of positive CSF cultures was 2.8 ± 0.8 versus 3.0 ± 0.9 days in the moxalactam and amikacin treatment group, respectively. The mortality and incidence of neurologic sequelae among survivors was similar for both treatment groups. Despite superior CSF penetration and improved bactericidal activity, the use of third-generation cephalosporins such as moxalactam and cefotaxime does not appear to have improved the outcome of neonatal meningitis [38, 39]. Alternative therapies to either increase the rate of bacterial killing or to modulate the CSF inflammation are needed to improve the prognosis of bacterial meningitis in the neonatal period.
Lebel
230
Table 1. Outcome of bacterial meningitis in 62 patients with H. injiuenzae meningitis treated with ampicillin [adapted from 19] Repeat CSF culture!
p value2
sterile (n = 48)
positive (n = 14)
Mean time of repeat lumbar puncture after start of therapy,h
27
26
more
Seizures during therapy
8%
50%
Adverse Outcome of Bacterial Meningitis due to Delayed Sterilization of Cerebrospinal Fluid Marc H. Lebel Department of Pediatrics and Microbiology-Immunology, Sainte-Justine Hospital, University of Montreal, Que., Canada
In the past two decades, there have been many changes in the choice of initial antibiotic therapy for treatment of bacterial meningitis in infants and children. Therapy has evolved from ampicillin alone to a combination of ampicillin plus chloramphenicol due to emergence of 13-lactamaseproducing strains of Haemophilus injluenzae type b. With the availability of newer generation cephalosporins at the beginning of the 1980s, many centers have been using second- and third-generation cephalosporins for meningitis caused by H. injluenzae, Streptococcus pneumoniae, Neisseria meningitidis or gram-negative enteric bacilli. Despite the availability of antimicrobial agents with increased in vitro activity and improvement in supportive care, bacterial meningitis still causes neurologic sequelae in a significant number of survivors [1-5]. This chapter summarizes the recent information on delayed cerebrospinal fluid (CSF) sterilization, how it adversely affects the outcome of patients with meningitis, and the factors involved in the delay of sterilization.
There is no standard definition for delayed CSF sterilization. A small percentage of infants and children with bacterial meningitis will have a CSF culture positive for bacteria on repeat lumbar puncture performed at 18-48 h after initiation of antibiotic treatment. In this article, CSF sterilization will be considered delayed when repeat CSF cultures are positive after 18-36 h of appropriate antibiotic therapy.
Downloaded by: Université de Paris 193.51.85.197 - 1/30/2020 4:24:10 PM
Definition of Delayed CSF Sterilization
Adverse Outcome of Bacterial Meningitis
227
The exact incidence of delayed CSF sterilization is difficult to determine from the literature because of the differences in timing of the followup lumbar punctures after initiation of therapy, dosing schedule of the antibiotics, and culture techniques. The ability to detect persistently positive CSF cultures after initiation of antibiotic therapy will depend on the culture technique used. For antibiotics that produce relatively low CSF bactericidal titers like ampicillin or cefuroxime, routine microbiologic techniques are sufficient. However, for antibiotics that produce high CSF bactericidal titers, like cefotaxime and ceftriaxone, special techniques (i.e., serial dilutions or inactivation of the antibiotic by addition of a cephalosporinase to the CSF sample) are needed. In one study using ceftriaxone, the CSF samples obtained 24 h after start of therapy were cultured with and without a cephalosporinase. All samples cultured in a routine manner (i.e., no cephalosporinase) were sterile, whereas 5% were positive when a cephalosporinase was added. With the newer generation f3-lactam compounds, rates of CSF sterilization from 90 to 100% have been reported when the repeat CSF cultures were done between 15 and 48 h after initiation of therapy [3-18]. Delayed CSF sterilization has been reported in 8-23% of patients treated with ampicillin [19- 23], 6-34% with chloramphenicol [5, 23, 24], 4-16% with cefuroxime [4,9, 10,25,26],2-5% with ceftazidime [11, 12], 0-9% with ceftriaxone [5, 13, 14,26,27]' and 2-7% with cefotaxirne [5, 15,28,29]. In a prospective multicenter trial, Peltola et al. [5] compared chloramphenicol, ampicillin, cefotaxime and ceftriaxone therapy for childhood bacterial meningitis. The CSF sterilization rates of each antibiotic is shown in figure 1. In this study, ceftriaxone appears to be the antimicrobial agent with the fastest sterilization rate. After 12 h of therapy, only 16% of ceftriaxone-treated patients had positive CSF cultures compared to 46% for all other antibiotics combined (p < 0.01) [5]. After 24 h of therapy, ceftriaxone and cefotaxime achieved similar rates of CSF sterilization. The faster CSF sterilization rate obtained with ceftriaxone in the early stages of treatment did not correlate with an improved clinical outcome. However, in other studies neurologic outcome did correlate with sterilization rate after 24 h of therapy [6, 19]. In Peltola's study [5], delayed CSF sterilization occurred significantly more often in the ampicillin plus chloramphenicol treatment group than in the ceftriaxone or cefotaxime treatment group. Three of 3 patients with S. pneumoniae meningitis treated with chloramphenicol had positive CSF cultures after 24 h of treatment. Treatment was extended or modified more frequently in the chloramphenicol group than in the other groups.
Downloaded by: Université de Paris 193.51.85.197 - 1/30/2020 4:24:10 PM
Incidence of Delayed CSF Sterilization
228
Lebel 100.-----------------------------~
Chloramphenicol Amplclliln Cefotaxime
..-. 80 ":!!.
Ceftriaxone
~
en UJ II:
:)
I-
60
...J
--I--------------------- -----
-----l-------~~--"~..
--_._----1---------"Ir--~--""!oiilI~------------·---
:)
0
LL
en
.'.
40
".
0
UJ
>
~
en 0
--
20
............ ~ .
D.
.......
•••••••••••::!
o+-------+-------~------~------~------~------~
Diagnosis
12 hours
24 hours
DURATION OF THERAPY Fig_ 1_ Sterilization of CSF after initiation of antibiotic therapy [adapted from
51-
Newborn In the neonatal period, sterilization of CSF is achieved easily in most patients with meningitis caused by gram-positive organisms. In a review of 16 patients with meningitis caused by Streptococcus agalactiae (group B Streptococcus), Listeria monocytogenes, enterococci and Staphylococcus, only 1 (6%) patient with L. monocytogenes meningitis had persistently positive CSF cultures despite adequate therapy [30]. Delayed CSF sterilization has been described in some infants with group B streptococcal meningitis [31-35]. Tolerance to penicillin might explain some of these cases [31]. Determination of minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) should be done on all meningeal isolates to detect tolerance to penicillin. However, failure to achieve prompt sterilization may be due to an inappropriate dose of an adequate antibiotic or the presence of an unsuspected suppurative focus
Downloaded by: Université de Paris 193.51.85.197 - 1/30/2020 4:24:10 PM
Adverse Outcome due to Delayed CSF Sterilization
Adverse Outcome of Bacterial Meningitis
229
Infants More than Three Months of Age and Children Children with H. injluenzae type b meningitis treated with ampicillin have a 6-fold increased risk of neurologic abnormalities including seizure disorders and cortical blindness at the time of discharge from the hospital if they have a positive CSF culture on repeat spinal tap after 19-36 h of therapy compared with those who have prompt eradication of the CSF pathogen (table 1). At follow-up examinations, patients with delayed CSF sterilization had a 6-fold increase in the incidence of neurological complications [19]. In that study, there were no differences in the demographic and clinical characteristics between the group with delayed or prompt sterilization and no correlation between severity of illness and
Downloaded by: Université de Paris 193.51.85.197 - 1/30/2020 4:24:10 PM
[32]. Despite prompt CSF sterilization in most infants with group B streptococcal meningitis, 20-50% of survivors have long-term sequelae [36, 37]. Delayed CSF sterilization occurs frequently in infants with meningitis caused by gram-negative bacilli [38, 39]. In one study, 59% (13/22) had positive CSF cultures for more 2 days after initiation of antimicrobial therapy [30] . At follow-up examinations 2-3 years after the episode of meningitis, 88% (7/8) of those with delayed CSF sterilization had detectable sequelae. In the First Neonatal Meningitis Collaborative Study, patients who expired (n = 11) had a statistically longer duration of positive CSF cultures (3.5 ± 0.4 vs. 2.0 ± 0.3 days) and days of interleukin-lJ3 concentrations> 200 ngll (3.3 ± 0.5 vs. 1.3 ± 0.3 days) than those that survived and had no sequelae (n = 18), respectively [40, 41]. In another report from the same group, the mean duration of positive CSF culture was 2.8 days in normal survivors versus 5.8 days in survivors with sequelae of Escherichia coli meningitis [42]. In the Third Neonatal Meningitis Cooperative Study Group, moxalactam and ampicillin were compared to amikacin and ampicillin therapy for meningitis caused by gram-negative enteric organisms in 63 infants [38]. The mean duration of positive CSF cultures was 2.8 ± 0.8 versus 3.0 ± 0.9 days in the moxalactam and amikacin treatment group, respectively. The mortality and incidence of neurologic sequelae among survivors was similar for both treatment groups. Despite superior CSF penetration and improved bactericidal activity, the use of third-generation cephalosporins such as moxalactam and cefotaxime does not appear to have improved the outcome of neonatal meningitis [38, 39]. Alternative therapies to either increase the rate of bacterial killing or to modulate the CSF inflammation are needed to improve the prognosis of bacterial meningitis in the neonatal period.
Lebel
230
Table 1. Outcome of bacterial meningitis in 62 patients with H. injiuenzae meningitis treated with ampicillin [adapted from 19] Repeat CSF culture!
p value2
sterile (n = 48)
positive (n = 14)
Mean time of repeat lumbar puncture after start of therapy,h
27
26
more
Seizures during therapy
8%
50%
