Niger J Paed 2013; 40 (1): 6 –14 REVIEW

Ogunlesi TA Diagnosis and treatment of bacterial in the newborn

DOI:http://dx.doi.org/10.4314/njp.v40i1.2 Accepted: 29th May 2012 Abstract Background: Bacterial riologic culture in the diagnosis of meningitis in the newborn is glob- meningitis can be improved with Ogunlesi, TA ( ) ally renowned for high mortality. serologic method like polymerase Department of Paediatrics, The associated morbidities also chain reaction. Widespread resis- Olabisi Onabanjo University Teaching include audiologic, motor, visual tance of may be threaten- Hospital, Sagamu P. O. Box 652, Sagamu-121001 and mental deficits. ing the use of and gen- Ogun State. Nigeria. Objective: To highlight the peculi- tamicin for empirical treatment of Email: [email protected] arities in the current diagnostic and newborn meningitis. No sufficient management strategies in newborn evidence presently supports the meningitis. current practices of fluid restriction, Methods: Relevant literature on the prolonged duration of subject published only in English treatment and non-use of adjuvant language or translated to English steroid therapies in the newborn. language was searched manually Conclusion: Efforts to reduce the and electronically. The Medline, incidence of newborn meningitis PUBMED and HINARI were cannot be separated from the pre- searched for the period between vention of newborn gener- 1966 and 2012. The following key ally. In addition, more controlled words were used during the search: trials are required in the developing newborn/neonatal, bacterial/ world with respect to the various pyogenic meningitis, central nerv- aspects of management of newborn ous system infections, , meningitis, particularly fluid man- dexamethasone and fluid agement and the use of adjuvant restriction. steroids. Results: The pattern of bacterial aetiology and mortality differ be- Keywords: Antibiotics, dexa- tween the developed and develop- methasone, meningitis, newborn, ing world. The usefulness of bacte- .

Introduction of neonatal meningitis in the middle belt was reported to be 1.9/1000 live births four and 6.5/ 1000 live births in Meningitis is an extensive inflammatory condition of the north-eastern Nigeria. 5 Similarly, the incidence rate leptomeninges. Although, it is generally described as reported in the Panama in the mid-nineties was 3.5 uncommon, meningitis occurs commonly in the neonatal cases/1000 live births. 6 period due to the increased susceptibility of newborn babies to severe infections.1 Neonatal meningitis is as- While the incidence has not changed remarkably, there sociated with significant mortality and severe morbid- has been a significant decrease in the mortality associ- ities. ated with meningitis over the last two decades due to improved antibiotic therapy and supportive care in most The overall incidence of meningitis in England and parts of the developed and industrialized world. On the Wales has not changed remarkably from the known 0.2 contrary, morbidity has not changed significantly over – 0.4 cases/1000 live births over the last three decades. this same period, even, in the developed world. The per- 2,3 These are similar to data obtained from other parts of sistently high morbidity rate among the survivors of the developed world. Although, consistent incidence neonatal meningitis remains a major clinical issue and rates are not available in most parts of the developing the need to minimize these morbidities is a challenge. 2,3 world, the few available ones are higher compared to the developed world. For instance, in Nigeria, the incidence Although, mortality rates in newborn meningitis vary by 7 region, the known rates in the various regions of the form the core of clinical diagnosis of meningitis in the world are not markedly different. For instance, mortality newborn. Due to the low sensitivity and specificity of rates included 0.7–1.9 ⁄ 1000 live births in sub-Saharan the clinical predictors of this severe infectious disease, Africa, 0.33–1.5 in the Middle East and North Africa laboratory diagnosis is indispensable. 12, 13 and 0.4-2.8 in the Americas and Caribbean. 7 Mortality in the developed world had dropped from close to 50% to Bacteriology of newborn meningitis about 10% over the last decade whereas morbidity Microbiology remains high at 15 to 60% among the survivors. 8 Although, under-reporting is a challenge in the develop- In consonance with sepsis, the bacterial aetiology of ing world, mortality associated with neonatal meningitis neonatal meningitis differs between the developing and also varies between 30% and 60% while morbidity fig- the developed world. In most developed countries, the ures vary greatly. Five to seven a high proportion of the leading in newborn meningitis is Group B survivors in neonatal meningitis develop chronic handi- (GBS). Others include , capping conditions with serious medical and psycho- , other coliforms and lately, social implications such as cerebral palsy, mental retar- .1, 8, 14 Data obtained from dation, disorder, hemiplegia, deafness and blind- England and Wales from 1985 to 1987 and from 1996 to ness. 5, 9 1997 showed very little change in the pattern of bacterial aetiology of neonatal meningitis over this period. GBS Although, bacterial meningitis is an important cause of accounted for 39% to 48% of all cases. Others included newborn death globally, the burden of neonatal sepsis Escherichia coli (18% to 26%), Streptococcus pneumo- and meningitis is most pronounced in the resource-poor niae (6%) and Listeria monocytogenes (5% to 7%). 2, 3 parts of the world where the disease constitutes a signifi- In a more recent French National survey, the leading cant proportion of neonatal admission and deaths. 10,11 pathogens in newborn meningitis included GBS (59%), In spite of the similarity in the pathology and patho- Escherichia coli (28%), Gram-negative bacilli apart genesis of meningitis in childhood, there are peculiari- from Escherichia coli (4%), other Streptococcus apart ties with regard to the diagnosis and management of from GBS (4%), Neisseria meningitidis (3%) and newborn bacterial meningitis. This review aims to high- Listeria monocytogenes (1.5%). 15 light the challenges in the diagnosis and management of bacterial meningitis in the newborn in comparison with The pattern of bacteriological aetiology in neonatal men- older children. Research issues which may possibly ingitis differs in terms of the spectrum of organisms as proffer solutions to the alarming high prevalence of neu- well as the relative prevalence of individual organisms rologic sequelae and poor quality of life among the sur- causing meningitis in most parts of the developing vivors of newborn bacterial meningitis will also be world. Escherichia coli was earlier reported as the lead- raised. ing aetiology in Nigeria 16 and more recently in Kenya. 17 Although E. coli was also commonly isolated in Nigeria, Diagnosis predominated in two other Nige- Symptoms and signs rian reports. 4, 5 In addition, some reports of GBS pre- dominance have also been made in parts of the develop- Bacterial meningitis can be extremely difficult to diag- ing world like Zimbabwe, Kenya and China. 17 - 19 Inter- nose in the newborn because the symptoms and signs estingly, none of the studies from Nigeria 4, 5, 16 reported are often subtle and non-specific at the early stage of the GBS as aetiology of neonatal meningitis. Even most disease. The clinical presentation of meningitis is indis- recent studies of newborn sepsis in Nigeria did not find tinguishable from that of sepsis without meningitis. The GBS or reported very few cases. 20 - 23 early symptoms of meningitis include pyrexia, poor feeding, , lethargy or irritability. These clinical Listeria monocytogenes is also uncommonly encoun- features may also characterize other newborn disorders tered in this part of the world. 17 On the other hand, such as hypoxic-ischaemic encephalopathy and meta- Gram negative bacilli (with the exception of E. coli ) bolic derangements such as hypoglycaemia. Therefore, have a global distribution but appear more common in distinguishing between early meningitis and other neo- the developing world, probably for reasons of poor hy- natal illnesses mentioned above may be challenging and giene. this is associated with the tendencies to frequently under -diagnose meningitis in the newborn. The emergence of unusual organisms like Haemophilus influenza in Nigerian babies with meningitis 5, 24 poses With the progression of the disease, bulging fontanelle, new challenges in the treatment of newborn meningitis shrill cry, apnoeas, , opisthotonus and coma may in this population. This organism is not usually taken occur. 12 Although, these features are more specific fea- into consideration when planning empirical antibiotic tures of meningitis and thus, facilitate diagnosis on clini- treatment for newborn meningitis in Nigeria. This may cal grounds, they occur quite late in the disease. Instruc- constitute technical delay in the commencement of ap- tively, the classic signs of meningeal irritation in the propriate antibiotic therapy in possible cases of Haemo- older children, such as neck stiffness and positive Ker- philus influenzae infection among newborns. nig sign or Brudzinski sign are often absent and unreli- The highlighted differences in the aetiology of meningi- able among infants. Thus, the latter features should not tis between the developed and developing world may be 8 explained in terms of population differences in the rate Similar caution has been raised with respect to CSF glu- and pattern of colonization, genetic differences in im- cose and protein concentrations among preterm babies mune response and differences in laboratory techniques with meningitis. 30 Indeed, there have been reservations for pathogen isolation and reporting. 7, 25 about the use of the CSF glucose and protein parameters in making the diagnosis of meningitis or assessing the Lumbar puncture success of treatment of meningitis because of the high variability in the values of the CSF parameters. 26 In a Positive bacteriologic culture of the large study, babies with meningitis had CSF cell count (CSF) is the gold standard diagnostic procedure for bac- of 0 to 15,900/mm 3, glucose ranging from 0 to 199mg/dl terial meningitis. In the absence of bacteriologic culture and protein ranging from 41 to 1964mg/dl compared to facilities, Gram stain of CSF may also provide useful 0 to 90,000/mm 3, 0 to 1089mg/dl and 3 to 4122mg/dl information upon which initial decisions on diagnosis respectively among normal babies. 26 Instructively, stud- and management can be based. Blood culture may also ies are yet to show to what extent this variability truly be positive in 40–60% of meningitis cases. 17, 19, 26 affects the diagnosis of meningitis in the newborn. In spite of the challenges posed by the variability high- The definitive method for diagnosis of meningitis lies in lighted above, most practitioners still stick to the tradi- the chemistry and bacteriologic culture of the CSF since tional cut-off values of the various parameters: white the clinical features of newborn meningitis are largely cell count > 32/mm 3 with more than 60% polymor- non-specific and blood culture may not always be as phonuclear cells, proteins > 170mg/dl in preterm babies stated above. There have been controversies about the (or > 150mg/dl among term babies) and glucose < 50% indications for lumbar puncture (LP) in newborn sepsis. of serum glucose, determined just prior to lumbar tap. Current concessions appear to be pivoted on the fact that, LP is only useful as part of the work-up for late- The Interpretation of neonatal CSF parameters is also onset sepsis or when infants with early-onset sepsis have difficult when the fluid is blood stained, as this obvi- clinical features suggestive of meningitis. Available ously changes both the cellular and biochemical con- evidence is not in support of the use of LP in routine stituents of the fluid. One of the traditional methods of sepsis work-up for healthy babies with presumed sepsis. resolving the debacle is to count both the erythrocytes 27 Unlike in the older child, raised intracranial pressure and leucocytes in the fluid and use the physiological rarely occurs in newborn meningitis since the open su- ratio of 700 erythrocytes to one leucocyte as the cut-off tures and fontanel allows expansion of the cranium point from normal. In a more recent US study, it was when pressure is building up. Thus, the exclusion of reported amongst others that, in a cohort of newborn elevated intracranial pressure prior to LP may not be a infants, CSF protein increased by 2mg/dl for every 1000 major concern in the newborn. Nevertheless, compro- erythrocytes in the CSF even in spite of the presence of mised cardio-respiratory functions are clear contraindi- pleocytosis. 31 This method may not require sophisti- cations to performing LP in critically ill infants. How- cated kits or personnel and thus, can be studied further ever, a modified left lateral position with the hip flexed for its clinical applicability in the developing world. to 90 ⁰ but without flexion of the neck has been proposed as useful for LP in the presence of respiratory embar- The CSF gets sterilized rapidly following exposure to rassment. 28 In all situations, when meningitis is sus- antibiotics. It takes just about two hours for meningo- pected, inability to perform LP should not delay appro- coccus, and up to six hours for pneumococcus. 32 This is priate antibiotic treatment. important in the situations of pre-hospital care antibiotic use which is common in parts of the world where antibi- When it is available, the CSF specimen should be exam- otic use is poorly regulated. The CSF culture findings ined macroscopically for turbidity and microscopically may be altered by prior antibiotic use but antibiotics for the presence of bacterial organisms. Instructively, rarely interfere with CSF protein or glucose. In this turbidity of the CSF is determined by the number of pus situation, bacterial antigen detection serological methods cells present in the fluid though the number may vary would be most useful. Even in the absence of prior ex- widely. Therefore, when clinical suspicion is strong, posure to antibiotics, delay in processing CSF for up to microscopic examination should take precedence over four hours, has been reported to cause progressive de- macroscopic examination. Although, Gram stain may cline in CSF glucose and white cell counts. 33 This is reveal the pathogens in more than three-quarter of cases, very relevant to the practice in the developing world bacteriological culture is the gold standard for diagnos- where inadequate laboratory services (in terms of per- ing meningitis in the absence of prior exposure to antibi- sonnel, infrastructures and equipment) may warrant de- otics. Abnormalities in cell count and biochemical pa- lays in processing CSF samples. Therefore, practitioners rameters such as glucose and proteins are also important in this part of the world need to take these variables into for making diagnosis. Due to physiological variations in consideration when interpreting CSF parameters. the biochemical and cellular parameters of newborn CSF, caution needs to be exercised in interpreting the To a large extent, the use of molecular and serologic parameters. The white cell counts in the newborn CSF methods such as the polymerase chain reaction (PCR), has been shown to be age-specific. 29 which does not require the presence of live organisms Thus, CSF cell count needs to be interpreted with cau- for diagnosis, have improved the diagnosis of meningitis tion in the diagnosis of neonatal bacterial meningitis. on the CSF. Commercial kits for performing the sero- 9 logic tests for Streptococcus pneumoniae , Group B platelets aggregation factor (PAF). These agents in turn, Streptococcus , E. coli and Haemophilus influenzae are offset an inflammatory cascade characterized by in- available in most laboratories in the developed world but creased vascular permeability, polymorphonuclear mi- not yet in the resource-poor parts of the developing gration and activities and production of exudates and world. PCR has been shown to detect 100% cases of cellular debris. Ultimately, these inflammatory events bacterial meningitis in a cohort of Greek children while result in cerebral oedema, elevated intracranial pressure, culture detected only 21.4%. 34 In addition, PCR, may, reduced cerebral perfusion, cerebritis, neuritis and vas- in the future be used to prognosticate since a study of culitis. 39 The end-result of all these pathologic features quantitative PCR on blood, showed a correlation be- include ischaemia, infarction and atrophy of neural tis- tween disease severity and meningococcal bacterial sues. Short and long-term morbidities occur in infants DNA load among older children. 35 Although, meningo- with bacterial meningitis as a result of the aforemen- coccus is not a common cause of newborn meningitis. tioned pathologic changes. Some of the acute morbid- However, it is very likely that a similar principle may ities in meningitis include cerebral oedema, subdural apply to other pathogens with respect to PCR and sever- effusion, subdural empyema, venous sinus thrombosis, ity of illness. cranial nerve palsies and hydrocephalus. Long term neu- rologic deficits in meningitis include hearing loss, corti- Neuro-imaging cal blindness, strabismus, speech disorders, behavioural disorders, motor deficits particularly hemiplegia, mental Neuro-imaging is required for the diagnosis of intra- retardation and seizure disorders. 5, 9 cerebral collections, structural focal lesions and ven- tricular dilatation. These features may affect response to Antibiotic treatment antibiotic treatment of meningitis. Therefore, poor clini- cal response despite adequate therapy is an indication The goal of antibiotic treatment in meningitis is rapid for neuro-imaging in newborn meningitis. The most sterilization of the CSF. This explains why antibiotic basic of such imaging method in use in the developing therapy is highly recommended when meningitis is world include trans-fontanelle ultrasonography and com- clinically suspected even when definite investigations puterized tomographic (CT) scans of the brain. Unfortu- are not feasible or delayed. In standard practice where nately, the wide variation in the size of normal lateral microbiological diagnosis could be reliably made, the ventricles make CT scans less reliable in diagnosing choice of antibiotic depends on the organism isolated. truly dilated ventricles in the newborn. 36 More efficient However, in most cases especially in most parts of the imaging facilities like the Magnetic Resonance Imaging developing world, the initial treatment is usually empiri- are unfortunately, not available for routine use in most cal pending the availability of sensitivity reports from centres in this part of the world. the laboratory. This empirical treatment depends on the known epidemiology of the likely organisms as well as Other investigations the local antibiotic resistance patterns. When the blood- brain barrier is inflamed as it occurs in meningitis, the Full blood count, C-reactive protein (CRP), clotting permeability is increased and the penetration of most studies, and urea and electrolytes are useful ancillary antibiotics into the CSF is improved. It is important that, tests in sepsis work-up. Leucopaenia and elevated CRP the antibiotic chosen for empirical treatment should have are known to be more consistent with the diagnosis of good penetration into the CSF and achieve adequate severe bacterial infection in the newborn. 37 Elevated minimum bactericidal concentration (MBC) for the or- procalcitonin (with sensitivity of 90% and specificity of ganism. 40 These properties are important for rapid ster- 65%) was recently shown, in a systematic review, to ilization of the CSF which impacts on the survival of the have good diagnostic accuracy especially for late-onset affected infants. sepsis where meningitis occur commonly. 38 The traditional treatment of neonatal meningitis involves Treatment and . Although, the penicillins generally have poor CSF penetration when the The three major aspects of treatment of bacterial menin- are inflamed, 41 adequate concentrations can be delivered gitis include (1) antibiotic therapy (2) fluid restriction into the CSF with more frequent and higher doses. (3) adjunctive therapy. Central to the understanding of On the other hand, gentamicin readily penetrates the the relevance of these major aspects is the basic pathol- inflamed blood-brain-barrier but rarely achieves the ogy and pathogenesis of bacterial meningitis. Following minimum bactericidal concentration for the pathogens. the penetration of pathogens into the subarachnoid Increasing the therapeutic dose of gentamicin in order to space, the destruction of the bacterial cell walls in the achieve higher minimum bactericidal concentration in meninges may occur spontaneously or following antibi- the CSF may be harmful since the drug ordinarily has a otic treatment. The destruction of the bacterial cell walls narrow therapeutic index and can readily cause ototoxic- results in the release of antigenic components such as ity and nephrotoxicity. 41 This is particularly challenging peptidoglycan and teichoic acid into the subarachnoid in the resource-constrained parts of the world where space. The released bacterial toxins and cell wall com- facilities for monitoring serum drug levels are not avail- ponents provoke the release of cytokines such as inter- able. In an attempt to circumvent this challenge, trials of leukins (IL-1β), tumour necrosis factor-γ (TNF) and intraventricular administration of antibiotics in meningi- 10 tis were conducted but the findings were disappointing shown to have high resistance to ampicillin and gen- with observed increased mortality. 42, 43 tamicin. 17, 19 These reports have significant implications for the principle of using ampicillin and gentamicin for The WHO recommended initial antibiotic combination the empirical treatment of newborn meningitis in this of a (e.g. ampicillin or penicillin G) and an part of the world. (e.g. gentamicin) or a third-generation cephalosporin (e.g. ceftriaxone or ) for the Duration of treatment and choice of antibiotic treatment of meningitis in young infants aged < 60days. 44 A recent systematic review 45 which compared Antibiotic therapy often requires modification once anti- the use of third generations and the traditional antibiot- biotic susceptibility testing becomes available. The anti- ics (ampicillin, penicillin and chloramphenicol in vari- biotic treatment of meningitis in the newborn is tradi- ous combinations), found no significant difference in tionally prolonged because of the challenges of penetra- terms of death, deafness and treatment failures among tion of CSF and achievement of minimum bactericidal subjects with meningitis. However, the review covered concentration earlier mentioned. At present, there is no all studies of bacterial meningitis irrespective of age statistical evidence to specifically guide the duration of hence the difficulty in generalizing the results of the antibiotic treatment in neonatal meningitis. However, review. the general principle is that the duration of antibiotic treatment depends on the organism isolated. For Gram In the developed world, the first line therapy is usually negative bacilli, parenteral administration of antibiotics ampicillin with gentamicin or ampicillin with cefo- should be continued for a minimum of three weeks or taxime or ceftriaxone although the latter has the ten- for 14 days after the sterilization of the CSF. 37 This dency to cause displace bilirubin from albumin binding prolongation of therapy is important because of delayed sites. 37 The third generation cephalosporins are effective sterilization of the CSF in Gram-negative bacilli menin- on a wide range of pathogens causing meningitis, in- gitis. The latter fact may explain the high mortality and cluding the aminoglycoside-resistant strains. Unfortu- poorer outcome associated with Gram negative bacilli nately, this class of antibiotics has not been shown to be meningitis. For GBS, the minimum duration of treat- particularly effective on Listeria monocytogenes , thus, ment is 14 days while Staphylococcus aureus meningitis they are not recommended for monotherapy in places should be treated for up to three weeks in order to re- where Listeriosis is common. Nevertheless, they have duce the risk of cerebral formation. good blood-brain-barrier penetration and achieve ade- quate minimum bactericidal concentrations for most It is recommended that LP should be repeated 24 to 48 organisms in the CSF. 46 Ampicillin is effective on GBS, hours after the commencement of therapy to ascertain the coliforms and Listeria monocytogenes . Although, sterilization of the CSF. However, with cefotaxime and Listeria monocytogenes and GBS are reportedly uncom- ceftriaxone, an Australian study of childhood meningitis mon in most parts of the developing world, most physi- demonstrated that the lowest CSF concentrations of both cians also adopt the combination of ampicillin and cefo- drugs were several times higher than the minimum bac- taxime in the empirical treatment of meningitis in the tericidal concentrations for the organisms newborn. The third-generation cephalosporins (meningococcus , pneumococcus and Haemophilus influ- (cefotaxime and ceftriaxone) are active against the major enzae ). 47 On the basis of these findings, the authors rec- pathogens of neonates worldwide, including aminogly- ommended that repeat LP was not necessary when treat- coside-resistant strains. A recent Nigerian study reported ing meningitis due to these organisms with either of remarkable sensitivity of pathogens in newborn septi- these drugs. Thus, it may be attractive to recommend caemia to ceftriaxone, cefotaxime and . 23 either of these drugs for the empirical treatment of new- Thus, these drugs can also be reliably used in the em- born meningitis in places where significant resistance to pirical treatment of meningitis. the drugs have not been reported and avoid repeat LP.

Antimicrobial resistance In some unusual cases, inflammatory changes in the CSF may persist despite adequate antibiotic treatment as Antibiotic resistance is a major challenge confronting a result of obstructive ventriculitis, subdural empyema, practitioners worldwide. 25 This, to a large extent, makes cerebral abscess or intracranial vessel thrombi. Persis- global recommendations on the choice of drugs which tent CSF is an indication for neuroimaging are useful for the empirical treatment of severe infec- and review of antibiotic therapy. From the results of tions in the newborn difficult. A recent study of new- neuroimaging, other therapeutic measures like surgical born septicaemia in Sagamu, Nigeria reported overall interventions may be required in the care of the meningi- resistance of 70.3% to ampicillin and 43.6% to gen- tic infant. In addition to neuroimaging, antibiotic ther- tamicin. 23 Specifically, the resistance of Staphylo- apy may need to be prolonged. Subsequent CSF exami- cocccus aureus to ampicillin and gentamicin were 66.7% nation is unnecessary if the CSF has been sterilized by and 37.5% respectively in the report from Sagamu. 48 hours of therapy and the clinical course has been This observation is important in view of the predomi- satisfactory. nance of Staphylococcus aureus as a leading pathogen in newborn meningitis as reported in another Nigerian Repeat LP at the end of therapy, hitherto recommended, study. 5 In addition, the Gram negative bacilli have been is currently unpopular in the UK. 48 A study of a small 11 number of babies also showed that a repeat LP was un- dexamethasone in improving the survival and reducing necessary if clinical response to treatment was satisfac- neurologic deficits including hearing loss in meningitis tory. This suggestion was based on the fact that neither among children, particularly in low-income countries. 55 normal CSF at the end of treatment nor abnormal CSF At present, the best evidence for the benefits of dexa- findings accurately predicted cure or relapse. 49 There- methasone is in H influenzae type b meningitis where fore, practitioners need to weight the benefit of a repeat better audiologic outcome has been clearly demon- LP at the end of treatment against the attendant risks. strated. 56

Trials of shorter duration of treatment are on-going Studies of the use of dexamethasone in meningitic new- among older children. A randomized trial among 100 borns are particularly sparse. Therefore, current treat- infants with meningitis showed that four days of ceftri- ment guidelines for newborn meningitis exclude adjunc- axone treatment is as effective as seven days with no tive dexamethasone therapy. Nevertheless, there are difference in complications and treatment failures.50 A reports of likely usefulness of dexamethasone in the more recent double-blind randomized trial in Malawi, reduction of overall mortality as well as reduction in showed no significant difference in relapse or treatment neurologic sequelae among survivors of newborn men- failure rate among children with meningitis treated with ingitis. A non-randomized study of Australian infants antibiotics for five days or 10 days. 51 This study sug- between 1953 and 1961 reported mortality rate of 41% gested that discontinuation of antibiotics after the fifth in the steroid-treated group compared with 75% of non- day of ceftriaxone among children of post-neonatal age treated group. Despite better survival, there was no im- who remained stable was safe. Similar trials in the new- pressive difference in the occurrence of neurologic se- born period are highly desired. quelae in both groups. 57 Another non-randomized study of newborns with bacterial meningitis in Nigeria be- Similarly, a randomized controlled trial of seven-day tween 1992 and 1995 revealed lower mortality and versus 14-day antibiotic treatment for neonatal sepsis higher frequency of full recovery among babies treated showed similar treatment failure rates in both groups with adjuvant dexamethasone. 5 These two studies, de- prompting a recommendation of shorter duration of spite their demonstration of usefulness of dexa- treatment. 52 For clinical usefulness, large scale con- methasone therapy in the newborn, could not be used as trolled trials are also required. It will be interesting to a universal guide for treatment because they were not know if these findings may be safely extrapolated to randomized controlled trials. Unfortunately, the most other invasive newborn diseases like meningitis. frequently cited study which questioned the usefulness of dexamethasone was randomized and controlled. 58 The Use of dexamethasone latter study of babies with meningitis in Jordan showed similar case fatality rates (22% Vs 28%) and neurologic Bacterial meningitis is characterized by high mortality sequelae (30% Vs 39%) among babies treated with or and severe neurologic sequelae among most survivors. It without dexamethasone. is believed that most of the sequelae are as a result of the damage to neural tissue during the acute inflammatory Several other studies among older infants and children process that characterizes bacterial meningitis. There- have demonstrated conflicting reports about the efficacy fore, the use of as adjuncts in the treat- of adjunct dexamethasone therapy in meningitis. 53, 59 The ment of bacterial meningitis is intended to attenuate the findings from these studies could not be scientifically acute inflammatory process, minimize tissue damage extrapolated to newborns because subgroup analysis was and ultimately improve clinical outcomes both in the not carried out for children aged 6 weeks to 12 weeks. short and long term. The extrapolation could have been useful given the un- derstanding that the immune characteristics and range of The timing of administration of corticosteroids in men- pathogens causing serious infections at that age (6 ingitis is also important in the determination of its effi- weeks to 12 weeks) are usually similar to those of the cacy. In childhood bacterial meningitis, the administra- newborn period. Nevertheless, till date, there is no clear tion of intravenous dexamethasone before or along with high-power statistical evidence that the use of corticos- the first dose of antibiotics has been reported to be more teroids in neonatal meningitis truly improves the out- beneficial compared to administration after the com- come and prevents neurologic complications of the dis- mencement of antibiotics. 53 It is standard practice to ease. Neither is there any clear high-power statistical administer dexamethasone in divided doses for four evidence that the use of corticosteroids in neonatal men- days. There is no evidence that the drug is more effec- ingitis truly lacks benefits in terms of the outcome of the tive when given for longer or shorter periods but the risk disease. Systematic reviews of the available controlled of adverse effects appears to increase with the duration trials are desired. of administration. 54 Use of intravenous fluids Although, the use of adjuvant corticosteroids has been traditionally employed in the treatment of meningitis Other important supportive care in the management of among children of post-neonatal age and adults, ran- meningitis includes anticonvulsant therapy, use of ino- domized and non-randomized studies have given con- tropes and fluid management. Unfortunately, there are flicting reports concerning the effectiveness of adjuvant no controlled clinical trials with respect to the use of 12 these measures among newborns. In general, it is a com- pressure are only used among older children who are mon practice to restrict fluids to two thirds or three quar- more at risk of significantly raised intracranial pressure ters of the daily maintenance during the management of as a result of non-expansible cranium. Osmotic agents childhood meningitis. The basis for this practice is the shift fluids from the extravascular to the intravascular need to reduce the likelihood of the syndrome of inap- space, resulting in a reduction of intracranial pressure. A propriate secretion of antidiuretic hormone (SIADH). recent study among children aged 2 months to 12 years SIADH is characterized by hyponatraemia, fluid reten- suggested that glycerol-induced increment in osmolality tion and a tendency to worsen cerebral oedema in men- and reduction in CSF volume may be mechanism by ingitis. Therefore, practitioners reduce fluid therapy in which glycerol reduces intra-cranial pressure. 63 Initial children with meningitis in the hope of preventing placebo-controlled trials of glycerol with or without SIADH. dexamethasone in childhood meningitis have demon- strated overall better neurologic sequelae among the The true benefits of this practice are yet to be docu- cases but not with respect to deafness. 64 More trials of mented. In the first place, the pathogenesis of SIADH in other osmotic diuretics such as 20% mannitol, glycerol meningitis remains unclear and the reported incidence of and hypertonic saline in the treatment of raised ICP are SIADH in meningitis varies considerably. These facts still on-going in different parts of the world. It may cast a lot of doubt on the usefulness of the practice of seem, by virtue of current knowledge, that meningitic fluid restriction in this instance. neonates do not desperately require osmotic therapy. However, controlled trials are still needed to prove this In addition, a significant proportion of children with assumption. meningitis particularly after delay in presentation pre- sents with dehydration or hypovolaemia and are in dire Prevention need of fluid resuscitation. 60 It will be dangerous to rig- idly restrict fluid therapy in such situation. Neonatal meningitis is characterized by high mortality Nevertheless, the clinical dilemma of whether fluids and severe morbidities which cause handicaps. A study should be restricted or not continues to generate dispari- of 111 children aged between 9 and 10 years who sur- ties in the pattern of clinical practice as well as difficul- vived neonatal meningitis in England and Wales be- ties in interpreting mortality figures in childhood menin- tween 1985 and 1989 showed worse general outcome gitis. compared to non-meningitic matched controls. The sur- vivors of neonatal meningitis had less mean intelligence Current thinking suggests that the increased extracellular quotient, higher frequency of motor impairment, sei- fluid, the appropriate increased secretion of ADH, and zures, hydrocephalus and hearing loss. 9 The spectrum of mild systemic hypertension occurring in situations of neurologic sequelae reported in the UK study was not raised intracranial pressure are compensatory mecha- different from the pattern reported from Nigeria. 5 nisms. These physiologic changes are required to over- come the raised intracranial pressure and to maintain Given the background of generally poor outcome in neo- adequate cerebral blood flow and perfusion. Therefore, natal meningitis, prevention is highly desired. The pre- fluid restriction is likely to reduce the efficacy of the ventive measures in newborn meningitis cannot be sepa- compensatory mechanisms and thus, increase the likeli- rated from those of newborn sepsis generally. These hood of adverse outcome. 61 A systematic reviews of may include routine screening of pregnant women for controlled trials among children showed no significant urinary tract infection, early intervention following difference in number of deaths and acute severe neuro- spontaneous rupture of fetal membranes and hygienic logical sequelae among maintenance-fluid and restricted birth generally. For the developed world and other -fluid groups. 62 Further subgroup analyses in the same places where GBS is reportedly predominant, prenatal review showed statistically significant difference in fa- screening for GBS, appropriate treatment and intrapar- vour of the maintenance-fluid group in terms of spastic- tum antibiotic prophylaxis are useful practices. 65 Instruc- ity, seizures at 72 hours and 14 days and chronic severe tively, these practices only reduce the burden of early- neurological sequelae at three-months follow up. onset neonatal disease whereas GBS meningitis com- The current body of scientific evidence no longer sup- monly presents as late-onset sepsis. ports the practice of fluid restriction in the management of childhood meningitis, as there are no benefits either Early recognition and prompt commencement of appro- immediately or on long term basis. Rather, it is more priate antibiotic therapy are also desired to minimize the attractive to carefully assess infants with meningitis for risk of poor outcome in neonatal meningitis. This consti- possible dehydration, correct dehydration appropriately, tutes major challenge in most parts of the developing ensure adequate fluid intake but prevent overhydration. world where most ill babies present late to the hospitals. The advent of vaccines against Haemophilus influenzae Treatment of raised intracranial pressure and Streptococcus pneumoniae infections might have changed the epidemiology of childhood meningitis in Raised intracranial pressure (ICP) is a well recognized the developed world but these have not impacted on the complication of meningitis among older children but newborn period where the vaccines are not routinely this is not a cause for concern among newborns with indicated. meningitis. Measures aimed at reducing intracranial 13 Conclusion evidences for guidance with respect to fluid manage- ment and use of steroids and osmotic agents in neonatal While efforts are on-going to reduce the incidence of meningitis. newborn meningitis in the resource-poor parts of the toworld, management strategies also need to be im- proved enhance survival and reduce neurologic seque- Conflict of interest: None lae among the survivors. To achieve this, more research Funding: None is coveted particularly with respect to optimal antibiotic therapy as earlier suggested. 66 Specifically, large scale, multi-centred controlled trials are desired to provide

References

1. World Health Organization. An- 11. Chowdhury HR, Thompson S, Ali 21. Mokuolu AO, Jiya N, Adesiyan timicrobial and support therapy for Mohammed, Alam N, Yunus M, OO. Neonatal septicaemia in bacterial meningitis in children. Streatfield PK. Causes of neonatal Ilorin: bacterial pathogens and Report of the meeting of 18-20 deaths in a rural subdistrict of antibiotic sensitivity pattern. Afr J June 1997, Geneva Switzerland. Bangladesh: Implications for inter- Med Med Sci 2002;31:127-130. WHO/CHD/98.6; WHO/EMC/ vention. Hlth Popul Nutr 22. Ojukwu JU, Abonyi LE, Ugwu J, BAC/98.2. 1998. 2010;28:375-382. Orji IK. Neonatal septicaemia in 2. Delouvois J, Blackbourn J, Hurley 12. Weber MW, Carlin JB, Gatchalian high risk babies in South-Eastern R et al. Infantile meningitis in S et al. Predictors of neonatal sep- Nigeira. J Perinat Med England and Wales: a two year sis in developing countries. Pedi- 2006;34:166-172. study. Arch Dis Child 1991;66: atr Infect Dis J 2003;22:711–716. 23. Ogunlesi TA, Ogunfowora OB, 603-607. 13. Best J, Hughes S. Evidence behind Osinupebi OA, Olanrewaju DM. 3. Holt D, Haket S, Louvouis JD et the WHO Guidelines: hospital care Changing trends in newborn sepsis al. Neonatal meningitis in England for children–what are the useful in Sagamu, Nigeria: Bacterial eti- and wales: ten years on. Arch Dis clinical features of bacterial men- ology, risk factors and antibiotic Child Fetal and Neonatal Ed ingitis found in infants and chil- susceptibility. J Paediatr Child 2001;84: F85–F89. dren? J Trop Pediatr 2008;54:83– Health 2011;47:5-11. 4. Airede AI. Neonatal bacterial men- 86. 24. Adeboye MA, Obasa TO, Fadeyi ingitis in the middle belt of Nige- 14. Chien HC, Chiu N, Li W, Huang A, Adesiyun OO, Mokuolu OA. ria. Dev Med Child Neurol F. Characteristics of neonatal bac- Haemophilus meningitis in an 1993;35:424-430. terial meningitis in a teaching hos- African neonate: time for active 5. Airede KI, Adeyemi O, Ibrahim T. pital in Taiwan from 1984-1997. J surveillance and institution of ap- Neonatal bacterial meningitis and Microbiol Immunol Infect propriate control measure. West dexamethasone adjunctive usage in 2000;33:100–104. Afr J Med 2010;29:275-277. Nigeria. Niger J Clin Pract 15. Gaschignard J, Levy C, Romain O 25. Osrin D, Vergnano S, Costello A. 2008;11:235-245. et al. Neonatal bacterial meningi- Serious bacterial infections in new- 6. Moreno MT, vargas S, Poveda R, tis: 444 Cases in 7 years. Pediatr born infants in developing coun- Saez-liorens X. Neonatal sepsis Infect Dis J 2000;30:212 – 217. tries. Current Opinion Infect Dis and meningitis in a developing 16. Longe C, Omene J, Okolo A. Neo- 2004;17:217–224. Latin American country. Pediatr natal meningitis in Nigerian in- 26. Garges HP, Moody A, Cotten M et Infect Dis J 1994;13:516-520. fants. Acta Paediatr Scand al. Neonatal Meningitis: what is 7. Stoll B. The global impact of neo- 1984;73:477–481. the correlation among cerebrospi- natal infection. Clin Perinatol 17. Laving AMR, Musoke RN, nal fluid cultures, blood cultures, 1997;24:1-21. Wasunna AO, Revathi G. Neonatal and cerebrospinal fluid parame- 8. Harvey D, Holt D, Bedford H. bacterial meningitis at the newborn ters? Pediatr 2006;117: 1094– Bacterial meningitis in the new- unit of Kenyatta national hospital. 1100. born: a prospective study of mor- East Afr Med J 2003;80:456–462. 27. Ajayi OA, Mokuolu OA. Evalua- tality and morbidity. Semin Peri- 18. Nathoo K, Pazvakavamba I, Chid- tion of neonates with risk for infec- natol 1999;23:218-225. ede O et al. Neonatal meningitis in tion/suspected sepsis: Is routine 9. Stevens JP, Eames M, Kent A, Harare, Zimbabwe: a 2-year re- lumbar puncture necessary in the Halket S, Holt D, Harvey D. Long view. Ann Trop Paediatr first 72 hours of life? Trop Med Int term outcome of neonatal meningi- 1991;11:11–15. Health 1997;2:284–8. tis. Arch Dis Child Fetal Neonatal 19. Chang CJ, Chang WN, Huang LT 28. Weisman LE, Merenstein GB, Ed 2003;88:F179-F184. et al. Neonatal bacterial meningitis Steenbarger JR. The effect of lum- 10. Ambe JP, Gasi IS, Mava Y. Re- in southern Taiwan. Pediatr Neu- bar puncture position in sick neo- view of neonatal infections in Uni- rol 2003;29: 288 – 294. nates. Am J Dis Child versity of Maiduguri Teaching 20. Adejuyigbe OE, Adeodu OO, Ako 1983;137:1077–9. Hospital: common bacterial patho- -Nai KA, Taiwo O, Owa JA. Septi- 29. Kestenbaum LA, Ebberson J, Zorc gens seen. Niger J Clin Pract caemia in high-risk neonates at a JJ, Hodinka RL, Shah SS. Defining 2007;10:290-293. teaching hospital in Ile-Ife, Nige- cerebrospinal fluid white blood ria. East Afr Med J 2001;78:540- count reference values in neonates and 543 . young infants. Pediatr 2010;125:257- 264.

14 30. Smith PB, Garges HF, Cotton CM, 41. Rang H, Dale M, Ritter J, Moore 53. Odio CM, Faingezight I, Paris M Walsh TJ, Clark RH, Benjamin P. Pharmacology, 5th edn. Chur- et al. The beneficial effects of early DK Jr. Meningitis in preterm neo- chill Livingstone, London.2003. dexamethasone administration in nates: importance of cerebrospinal 42. McCracken GH, Mize SG, infants and children with bacterial fluid parameters. Am J Perinat Threlkeld N. Intraventricular gen- meningitis. New Eng J Med 2008;25:421-426. tamicin therapy in gram-negative 1991;324:1525 – 1531. 31. Hines EM. Nigrovic LE, Neuman bacillary meningitis of infancy. 54. McIntyre PB, Berkey CS, King MI, Shah SS. Adjustment of cere- Report of the Second Neonatal SM et al. Dexamethasone as ad- brospinal fluid protein for red Meningitis Cooperative Study junctive therapy in bacterial men- blood cells in neonates and young group. Lancet 1980;1:787-791. ingitis. A meta-analysis of random- infants. J Hosp Med 2012;7:325- 43. Shah SS, Ohlsson A, Shah VS. ized clinical trials since 1988. 328. Intraventricular antibiotics for JAMA 1997;278:925 – 931. 32. Kanegaye JT, Soliemanzadeh P, bacterial meningitis in neonates. 55. Van de Beek D, de Gans J, McIn- Bradley JS. Lumbar puncture in Cochrane Database of Systematic tyre P, Prasad K. Corticosteroids pediatric bacterial meningitis: Reviews 2008 Issue 4, Art No.: for acute bacterial meningitis. defining the time interval for re- CD004496 Cochrane Database of Systematic covery of cerebrospinal fluid 44. WHO. Pocket Book of Hospital Reviews 2007 24(1): CD004405. pathogens after parenteral antibi- Care for Children - Guidelines for 56. Schaad UB, Lips U, Gnehm HE, et otic pretreatment. Pediatr the Management of Common Ill- al. Dexamethasone therapy for 2001;108:1169–74. nesses with Limited Resources. bacterial meningitis in children. 33. Rajesh NT, Dutta S, Prasad R, World Health Organisation, Ge- Lancet 1993;342:457–61. Narang A. Effect of delay on neo- neva. 2005. 57. Yu JS, Grauaug A. Purulent men- natal cerebrospinal fluid parame- 45. Prasad K, Kumar A, Singhal T, ingitis in the neonatal period. Arch ters. Arch Dis Child Fetal Neoona- gupta PK. Third-generation cepha- Dis Child 1963;38: 391 – 396 tal Ed 2010;95:F25-F29. losporins versus conventional anti- 58. Daoud AS, Batieha A, Al-Sheyyab 34. Papavasileiou K, Papavasileiou E, biotics for treating acute bacterial M, Abuekteish F, Obeidat A, Tzanakaki G, Voyatzi A, Kre- meningitis. Cochrane Database of Mahafza T. Lack of effectiveness mastinou J, Chatzipanagiotou S. Systematic Reviews 2007 Issue 4, of dexamethasone in neonatal bac- Acute bacterial meningitis cases Art No.: CD001832. terial meningitis. Eur J Pediatr diagnosed by culture and PCR in a 46. Cherubin CE, Eng RHK, Norrby 1999;158: 230 – 233. children’s hospital throughout a 9- R, Modai J, Humbert G, Overturf 59. Molyneux EM, Walsh AL, Forsyth year period (2000-2008) in Athens, G. Penetration of newer cepha- H et al. Dexamethasone treatment Greece. Mol Diagn Ther losporins into cerebrospinal fluid. in childhood bacterial meningitis 2011;15:109-113. Rev Infect Dis 1989;11: 526–546. in Malawi: a randomized con- 35. Hackett SJ, Guiver M, Marsh J, et 47. Goldwater PN. Cefotaxime and trolled trial. Lancet 2002;360: 211 al. Meningococcal bacterial DNA ceftriaxone cerebrospinal fluid – 218. load at presentation correlates with levels during treatment of bacterial 60. Prince AS, Neu HC. Fluid manage- disease severity. Arch Dis Child meningitis in children. Int J Antim- ment in Hameophilus influenza 2002;86:44–6. icrob Agents 2005;26:408-11. meningitis. Infect 1980;8:5–7. 36. Haslam RH. Role of computed 48. Agarwal R, Emmerson AJ. Should 61. Singhi SC, Singhi PD, Srinivas B, tomography in the early manage- repeat lumbar punctures be rou- et al. Fluid restriction does not ment of bacterial meningitis. J tinely done in neonates with bacte- improve the outcome of acute Pediatr 1991;119:157–9. rial meningitis? Results of a survey meningitis. Pediatr Infect Dis J 37. Stephenson T, Marlow N, Watkin into clinical practice. Arch Dis 1995;14:495–503. S, Grant J (eds). Fetal and neonatal Child 2001;84:451–2. 62. Maconochie IK, Bauner JH, Stew- infection. In: Pocket . 49. Schaad UB, Nelson JD, art M. Fluid therapy for acute bac- 1st ed. Edinburgh: Churchill Liv- McCracken GH Jr. Recrudescence terial meningitis. Cochrane Data- ingstone, 2008:241-69. and relapse in bacterial meningitis base of Systematic Reviews 2008, 38. Vouloumanou EK, Plesssa E, kara- of childhood. Pediatr 1981;67:188 Issue 1 Art No.: CD004786 georgopoulos DE, Mantadakis E, –95. 63. Singhi S, Jarvinen A, Peltola H. Falagas ME. Serum procalcitonin 50. Roine I, Ledermann W, Foncea Increase in serum osmolality is as a diagnostic marker for neonatal LM, et al. Randomised trial of four possible mechanism for the benefi- sepsis: a systematic review and vs seven days of ceftriaxone treat- cial effects of glycerol in child- meta-analysis. Intensive Care Med ment for bacterial meningitis in hood bacterial meningitis. Pediatr 2011;37:747-762. children with rapid initial recov- Infect Dis J 2008; 27: 892-896. 39. Mustafa MM, Ramilo O, Saez ery. Pediatr Infect Dis J 64. Peltola H, Rome I, Fernandez J et Liorens X, Olsen KD, Magness 2000;19:219–22. al. Adjuvant glycerol and/or dexa- RR, McCracken GH Jnr. Cerebro- 51. Molyneux E, Nizami SQ, Saha S methasone to improve the outcome spinal fluid prostaglandins, inter- et al. 5 versus 10 days of treatment of childhood bacterial meningitis: leukins-1 beta and tumor necrosis with ceftriaxone for bacterial men- a prospective, randomized, double- factor in bacterial meningitis: ingitis in children: a double-blind blinded, placebo-controlled trial. clinical and laboratory correlations randomized equivalence study. Clin Infect Dis 2007;45:1277-12686. in placebo treated and dexa- Lancet 2011;377:1837-1845. 65. American Academy of Pediatrics. methasone treated patients. Am J 52. Chowdhary G, Dutta S, Narrang Revised guidelines for prevention of Dis Child 1990;144: 883 – 887. A. Randomized controlled trial of early-onset Group B Streptococcal 40. Tauber MG, Sande MA. General 7-day vs 14-day antibiotics for infection. Pediatr 1997;99:489–96. 66. Furyk JS, Swann O, Molyneux E. principles of therapy of pyogenic neonatal sepsis. J Trop Pediatr Systematic review: neonatal meningitis meningitis. Infect Dis Clin North 2006;52:427-432. in the developing world. Trop Med Int Am 1990;4:661–76. Health 2011;16:672 – 679.