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## **Meet the editor**

Professor Dr Sir George Wireko-Brobby was born in 1942 in Ghana. He studied at the University of Marbug, West Germany from 1964 to 1973. He graduated in Medicine and Dentistry by a double doctoral Dissertation with Magna cum Laude in both areas. George Wireko Brobby is a Professor of Otorhinolaryngology (ENT) and past Dean of the School of Medical Science KNUST Kumasi Ghana. He is the current President of the Ghana Postgraduate College of Physicians and Surgeons. He is a teacher at the undergraduate and postgraduate level and internal assessor at the West African College of Surgeons and the Ghana College of Physicians and Surgeons in his field of Ear, Nose and Throat Surgery. Prof Brobby was appointed as a WHO Consultant on Prevention of Deafness and Hearing Impairment in 1996. He has travelled far and wide and collaborated with Institutions, ENT Department of Kenya, Zambia, Ethiopia, Tanzania, Sheffield, UK, Liverpool, UK, Universities of Ulm and Dusseldorf, Germany, Cyprus, New Delhi, India and Malta. Sir George is Associate Editor in the Journal of Hearing International, Japan and a member of the Editorial Board of the Ghana Medical Association. He is also a co-Editor of the British Medical Journal - African Edition and a member of the AdvisoryBoard of KNUST Journal. His international experiences include his appointment as the President Initiative for Deaf Education in Commonwealth countries from 1990-1998, Secretary General of the Pan African Federation of Otolaryngological Societies (PAFOS), culminating in his election as President of PAFOS form 1999-2004.

### Contents

#### **Preface XI**

### Preface

This book focuses on two primary objectives. It aims to provide general practitioners, paediatricians, and specialist physicians with an essential text written in an accessible language, and also to highlight the differences in pathogenesis and causative agents of meningitis in the developed and the developing world.

Meningitis is a medical emergency requiring a rapid diagnosis and an immediate transfer to an institution supplied with appropriate antibiotic and supportive measures.

Especially in the developing world, where malaria is rampant, one must maintain a high level of caution when confronted with a febrile child or one who has an altered mental status, as the first ten hours of care may make a crucial difference in the outcome.

Bacterial or purulent meningitis is the most important form of infection in the United States in terms of incidence, sequela and ultimate loss of productive life.

Aseptic meningitis, usually caused by a virus, is also common, however significant sequela are rare and the disease is self-limiting.

In Sub-Saharan Africa, seasonal outbreaks and epidemics of meningitis and septicaemia numerically present the greatest public health impact on the continent.

The three polysacharide encapsulated bacteria for which licensed vaccines are curable are Pneumococcus, Haemophilius influenza type b (Hib) and the Neisseia Meningococcus. They are also the most common causative agents of bacterial meningitis in Sub Saharan Africa.

Especially in South Africa, granulomatous meningitis, caused either by *M. tuberculosis* or fungi is a major cause of neurologic injury and death.

The necessary factors to consider for the epidemiology of the disease include age, ethnicity, season, host factors and regional pattern of the antibiotic resistance among likely pathogens.

The first month after birth represents the period of highest attack rate for meningitis with likely pathogens including *S. agalactiae*(group B streptococcus), *E. coli*, other gram X Preface

negative enteric organisms, and *L. monocytogenes*. Beyond the neonatal period the most important pathogens are *H. influenza* type B, 1 up to 6 years of age, *N. menigococcus* and *S. pneumoniae*.

In the US and Europe, the disease is reported with increased frequency among African Americans, Native Americans and individuals in rural areas.

Even in Africa, patients with poor socio-economic factors suffer more from the devastating effects of meningitis. In West Africa, the meningitis belt passes through the Northern part of the countries where people live in overcrowded huts. It has been documented that especially in the dry season, meningococcal, pneumococcal and Haemoiphilus infection spread by the respiratory route, which is aided by overcrowding. It has also been documented that host factors predisposing the infection include congenital or Acquired Immune Deficiency status, Sickling Haemoglobinopathies, chronic liver or renal disease. The classic triad of symptoms in meningitis is fever, headache, and stiff neck. However in children under 2 years of age, stiff neck or other signs of meningial irritation may be absent. Alterations level of consumers is a common finding present in up to 90% of patients.

In this book a detailed chapter on laboratory findings has also been provided.

Once meningitis is suspected, an immediate examination of the CSF is indicated, except if a strong suspicion of an intracranial mass lesion is present, where lumbar puncture may be delayed until a CT scan or an MRL has been done.

Effective treatment of meningitis depends on early aggressive supportive therapy and a selection of empiric antimicrobials appropriate for the likely pathogens.

In Europe and the USA, 1 third generation cephalosporine has become the first-line therapy, but while these drugs remain relatively expensive, it is probably reasonable for most African hospitals to continue with the combination of a peniciline and chloramphenicol as initial therapy as long as clinicans are aware of the risk of recondescences, particularly if steroids are used.

Common neurological complications in both adults and children are motor deficit, cognition deficit, hemiplegia epilepsy, developmental and learning disabilities, including blindness and deafness. A special chapter on the devastating effects of sensorineural hearing loss and the benefits of early rehabilitation is also included in this book.

#### **Prof. Dr. Dr. Sir George Wireko-Brobby**

President of the Ghana Postgraduate College of Physicians and Surgeons Professor of Otorhinolaryngology, Department of Eye, Ear, Nose and Throat, School of Medical Science, KNUST, Kumasi, Ghana

X Preface

*S. pneumoniae*.

negative enteric organisms, and *L. monocytogenes*. Beyond the neonatal period the most important pathogens are *H. influenza* type B, 1 up to 6 years of age, *N. menigococcus* and

In the US and Europe, the disease is reported with increased frequency among African

Even in Africa, patients with poor socio-economic factors suffer more from the devastating effects of meningitis. In West Africa, the meningitis belt passes through the Northern part of the countries where people live in overcrowded huts. It has been documented that especially in the dry season, meningococcal, pneumococcal and Haemoiphilus infection spread by the respiratory route, which is aided by overcrowding. It has also been documented that host factors predisposing the infection include congenital or Acquired Immune Deficiency status, Sickling Haemoglobinopathies, chronic liver or renal disease. The classic triad of symptoms in meningitis is fever, headache, and stiff neck. However in children under 2 years of age, stiff neck or other signs of meningial irritation may be absent. Alterations level of

Americans, Native Americans and individuals in rural areas.

consumers is a common finding present in up to 90% of patients.

puncture may be delayed until a CT scan or an MRL has been done.

recondescences, particularly if steroids are used.

this book.

a selection of empiric antimicrobials appropriate for the likely pathogens.

In this book a detailed chapter on laboratory findings has also been provided.

Once meningitis is suspected, an immediate examination of the CSF is indicated, except if a strong suspicion of an intracranial mass lesion is present, where lumbar

Effective treatment of meningitis depends on early aggressive supportive therapy and

In Europe and the USA, 1 third generation cephalosporine has become the first-line therapy, but while these drugs remain relatively expensive, it is probably reasonable for most African hospitals to continue with the combination of a peniciline and chloramphenicol as initial therapy as long as clinicans are aware of the risk of

Common neurological complications in both adults and children are motor deficit, cognition deficit, hemiplegia epilepsy, developmental and learning disabilities, including blindness and deafness. A special chapter on the devastating effects of sensorineural hearing loss and the benefits of early rehabilitation is also included in

> President of the Ghana Postgraduate College of Physicians and Surgeons Professor of Otorhinolaryngology, Department of Eye, Ear, Nose and Throat,

**Prof. Dr. Dr. Sir George Wireko-Brobby**

School of Medical Science, KNUST, Kumasi,

Ghana

### **Bacterial Meningitis and Deafness in Sub-Saharan Africa**

George Wireko-Brobby

*College of Health Science, School of Medical Sciences, KNUST, Kumasi Ghana*

#### **1. Introduction**

Bacterial Meningitis is a leading cause of childhood Deafness in Ghana and the sub- Saharan Africa. Children are predominantly at risk of bacterial meningitis mainly because of their immature immune system, and malnutrition especially in our part of the world. Lack of immunization practices also makes them more susceptible to significantly high morbidity and mortality.

Even with the provision of highly effective antibiotic therapy, death and long-term disabilities are the common but still serious consequences of acute bacterial meningitis in developing countries.

Common neurological complications in both adult and children are motor deficit, cognition deficit, hemiplegia, epilepsy, developmental and learning disabilities, blindness and Deafness.

In this chapter, we shall focus more on the devastating effects of sensorineural Hearing loss or Deafness, after bacterial meningitis. Delay in the Diagnosis of Hearing loss occurs firstly because language development of Hearing impaired children, parallels that of normal infants till the age of nine months. Secondly, because children with profound hearing loss coo and bable until this age, the parents are likely to ignore any subtle evidence of hearing impairment such as lack of response to environmental sound. Damage to the Cochlea, occurs in the early stages of the illness and it is often permanent and irreversible. Woodrow & Brobby (1997); Daya et al. (1998).

Prevention of deafness relies on early treatment with appropriate antibiotics, but adjunctive treatment with dexametnasore though controversial may be useful in preventing the sequel of sensorineural Hearing loss. In the long term vaccinations may be the most practicable means to reducing the burden of meningitis in the developing countries of Africa.

Facilities for audiological assessment and management of children recovering from meningitis are crucial for the detection of significant hearing impairment and the implementation of rehabilitation programmes.

Our observation at our University Teaching Hospital (KATH) is that about 20% of patients who survive with neurological sequelae, permanent sensorineuraal Hearing loss, accounts for approximately 75% of these cases.

In a study on causes of Deafness in Ghana, Brobby (1998) Meningitis was rated the 3rd amongst other childhood infections. Recent observations predict that meningitis has taken the 2nd position after measles.

This is worrying because even a mild hearing loss of less than 40 Db may have long-term developmental consequences. Given the scale of this problem, there is the need to review critically our knowledge about the natural history of the hearing loss which may follow meningitis and to discuss the applicability of recent therapeutic interventions studied in industrial nations to the diseases in the African contest.

#### **2. Microbiology**

In Africa, acute bacterial meningitis has an overall annual endemic rate in the region of 10- 50 per 105 populations, a figure at least 10 times that for Europe and the United States, and this disparity appears to be growing. Fortnum (1992). More than 70 per cent of cases are caused by either Streptococcus pneumonia (pneumococcal) or Neisseria meningitides (meningococcal). Haemophius influenza type b (Hib) is responsible for fewer cases in the population as a whole although it is a major problem in children less than 12 months of age, Airede (1993).

Epidemics of meningococcal meningitis sweep through the sub-Saharan 'meningitis belt' every 8 to 12 years. Annual incidence may reach 1 per cent of the population in certain areas.

Although this review concentrates on acute bacterial meningitis in Ghana, tuberculous meningitis is also relatively common in certain areas and is the leading cause of meningitis in the Western Cape Province of South Africa, where deafness. Deafness is a wellrecognized complication. From our experience, viral meningitis has only rarely been associated with deafness.

In Africa seasonal outbreaks and epidemics of meningecal meningitis and septicaemia, numerically represent their greatest public health impact on the continent.

In Ghana, the three polysaccharide encapsulated bacteria for which licensed vaccines are curable are Pneumococcus, Haemophilus influenza type b (Hib) and the Neisseria Menigococcus. Our observation is that Haemophilus influenza type b is responsible for fewer cases of meningitis in our sub-region.

#### **3. Epidemiology**

A number of factors appear to influence the frequency of post-meningitis hearing loss but it is not possible to predict hearing loss accurately in individual cases. Factors affecting this figure including the causative organism, the pneumococcus causing the highest rate of deafness (31.8 per cent) in comparison with the meningococcus (7.5 per cent) and Hib (11.4 per cent) All ages may develop deafness – the fact that most cases occur in infants may reflect their greater susceptibility to severe infection rather than a particular vulnerability to hearing impairment. At a community level, meningitis is one of the most common causes of hearing loss. In Kumasi, Ghana, meningitis is responsible for 8.5 per cent of cases of sensorineural hearing impairment in children.Brobby (1998)

#### **4. Natural history**

2 Meningitis

Our observation at our University Teaching Hospital (KATH) is that about 20% of patients who survive with neurological sequelae, permanent sensorineuraal Hearing loss, accounts

In a study on causes of Deafness in Ghana, Brobby (1998) Meningitis was rated the 3rd amongst other childhood infections. Recent observations predict that meningitis has taken

This is worrying because even a mild hearing loss of less than 40 Db may have long-term developmental consequences. Given the scale of this problem, there is the need to review critically our knowledge about the natural history of the hearing loss which may follow meningitis and to discuss the applicability of recent therapeutic interventions studied in

In Africa, acute bacterial meningitis has an overall annual endemic rate in the region of 10- 50 per 105 populations, a figure at least 10 times that for Europe and the United States, and this disparity appears to be growing. Fortnum (1992). More than 70 per cent of cases are caused by either Streptococcus pneumonia (pneumococcal) or Neisseria meningitides (meningococcal). Haemophius influenza type b (Hib) is responsible for fewer cases in the population as a whole although it is a major problem in children less than 12 months of age,

Epidemics of meningococcal meningitis sweep through the sub-Saharan 'meningitis belt' every 8 to 12 years. Annual incidence may reach 1 per cent of the population in certain

Although this review concentrates on acute bacterial meningitis in Ghana, tuberculous meningitis is also relatively common in certain areas and is the leading cause of meningitis in the Western Cape Province of South Africa, where deafness. Deafness is a wellrecognized complication. From our experience, viral meningitis has only rarely been

In Africa seasonal outbreaks and epidemics of meningecal meningitis and septicaemia,

In Ghana, the three polysaccharide encapsulated bacteria for which licensed vaccines are curable are Pneumococcus, Haemophilus influenza type b (Hib) and the Neisseria Menigococcus. Our observation is that Haemophilus influenza type b is responsible for

A number of factors appear to influence the frequency of post-meningitis hearing loss but it is not possible to predict hearing loss accurately in individual cases. Factors affecting this figure including the causative organism, the pneumococcus causing the highest rate of deafness (31.8 per cent) in comparison with the meningococcus (7.5 per cent) and Hib (11.4 per cent) All ages may develop deafness – the fact that most cases occur in infants may reflect their greater susceptibility to severe infection rather than a particular vulnerability to

numerically represent their greatest public health impact on the continent.

for approximately 75% of these cases.

industrial nations to the diseases in the African contest.

the 2nd position after measles.

**2. Microbiology**

Airede (1993).

associated with deafness.

**3. Epidemiology**

fewer cases of meningitis in our sub-region.

areas.

Sensorineural heating loss is typically bilateral, and occurs within 48 hours of the development of meningitis, with the majority of children who go on to suffer permanent damage having abnormal hearing tests on admission to hospital. There appears to be an initial phase of mild, reversible damage. Significant sensorineural hearing loss persisting after the acute phase of the illness is characteristically permanent although cases of partial recovery have been documented on certain occasions. Mild, temporary, conductive deficits are common in the recovery phase. Pathological correlates for these clinical findings are still lacking but potential pathophysiological mechanisms are discussed below.DAYA et al (1997)

#### **5. Pathology**

The auditory lesion in post-meningitic hearing loss remains obscure. It is likely that more than one mechanism of auditory pathway damage occurs. A body of clinical and experimental evidence suggests that the cochlea is the most frequent site of sensorineural damage, bacteria gaining access to the labyrinth via the cochlear aqueduct. DAYA et al (1998) Cell wall components directly toxic to cochlear hair cells, setting up a serous labyrinthitis In addition, these components also stimulate the inflammatory response, leading to suppurative labyrinthitis and permanent damage; in severe cases the labyrinth may be completely obliterated and neo-ossification occurs. The vestibular apparatus is commonly damaged in conjunction with this process. Other potential mechanisms of deafness include septic thrombophlebitic or embolisation of blood vessels supplying the inner ear and damage to the VIIIth cranial never or central auditory pathways.

#### **6. Diagnosis**

Screening for deafness during hospitalization is an accurate predictor of hearing impairments at follow-up, and ideally should be performed on all cases. It is also important to examine the middle ear with tympanometry in order to assess conductive impairments, which can be expected to improve with time. A follow-up assessment at approximately 6 weeks, when acute inflammation has subsided, confirms the degree of sensorineural damage and allows appropriate rehabilitation to be instituted. Assessment of hearing loss following meningitis is currently based on audiometric methods. Unfortunately the inaccuracy of age-appropriate tests in healthy children, the infants' lack of consistent response to sound and the effect of associated motor disorders tend to impair the validity of audiometry. More objective methods such as Brainstem Audiometry Evoked Responses (BAERs) and Oto-Acoustic Emissions (OAEs) have yet to reach the clinic in most parts of the continent.

More objective methods such as Brainstean Auditory Evoked responses (BAERs) and Oto-Acustic Emulsions (OAEs) are the latest state of the art equipments for this purpose. (DAYA et, al 1998)

Fortunately, the Kumasi Hearing Assessments Centre established through the magnificent generosity of the Commonwealth Society for the Deaf is the only centre, recognized by the WHO, in Africa, South of the Sahara which has all these facilities.

#### **7. Acute management**

Prompt Empirical antibiotic treatment should include Agents active agent all main pathogens for the eradication of the infecting organism in order to ensure optimal outcome. The introduction of sulphonamides in the 1950s (primarily for meningococcal meningitis) and of penicillins in the 1960s had a striking effect on incidence of mortality and mobility. The spread of plasmid-borne betalactamases in Hib led to the addition of chloramphenicol to therapy. This combination is still standard in most African countries. The latest challenge to this regimen has been the relatively recent appearance of penicillin-resistant pneumococci and meningococci. Further, some pneumococci are also chloramphenicol-resistant. This will undoubtedly affect the choice of antibiotics although the number of studies documenting a worsening clinical outcome is still small. In Europe and the USA third-generation cephalosporins have become first-line therapy but while these drugs remain relatively expensive, it is probably reasonable for most African hospitals to continue with the combination of a penicillin and chloramphenicol as initial therapy as long as clinicians are aware of the risk of recrudescence, particularly if steroids are being used. Friedland 1998.

A large number of clinical trials have been performed addressing the issue of whether steroids reduce the frequency of adverse outcomes, particularly hearing loss. It is not possible to discuss these studies in detail here, but certain points should be borne in mind when considering the evidence for and against steroids. Most trials could be criticized on methodological grounds because data were analysed without pre-defined end-points, allowing multiple comparisons to be made. In the three trials where significant results have been obtained, there were unusually high incidences of adverse outcome in the placebo group. Furthermore, no study with a consistent antibiotic regimen throughout has shown statistically significant reduction in hearing loss. Despite these problems, the case for giving dexamethasone in Hib meningitis is felt by many authorities to be strong. The role for dexamethasone in pneumococcal and meningococcal disease is at present unresolved.

Many of the trials of both dexamethasone and antibiotic regimens have been performed in the United States, with Hib as the dominant aetiology and so considerable caution should be exercised when applying conclusion to the African setting A recent reported trial in Pakistan found no evidence that dexamethasone was beneficial and suggested that it may be deleterious in this setting. Quazy (1996) Airede (2008)

The finding of different outcomes in various settings is not uncommon. There are clearly huge differences in terms of population, genetics, and timing of presentation, microbiology and general supportive care which can explain this apparent discrepancy. Giving the added cost of dexamethasone to the family of a patient who has already begun receiving two antibiotics, we feel that there is insufficient evidence at this time to recommend routine use of dexamethasone for acute bacterial meningitis of unknown cause.

Currently, the recommended empirical treatment of meningitis is ampicillin plus an aminoglycoside and a third generation cephalosporin.

The use of dexamethasore remains controversial. But our experience at KATH suggests that initial Doses of 50mg Hydrocartison before the administration of the antibiotics help to reduce the occurance of Sensorineural hearing loss.

#### **8. Discussion**

4 Meningitis

Fortunately, the Kumasi Hearing Assessments Centre established through the magnificent generosity of the Commonwealth Society for the Deaf is the only centre, recognized by the

Prompt Empirical antibiotic treatment should include Agents active agent all main pathogens for the eradication of the infecting organism in order to ensure optimal outcome. The introduction of sulphonamides in the 1950s (primarily for meningococcal meningitis) and of penicillins in the 1960s had a striking effect on incidence of mortality and mobility. The spread of plasmid-borne betalactamases in Hib led to the addition of chloramphenicol to therapy. This combination is still standard in most African countries. The latest challenge to this regimen has been the relatively recent appearance of penicillin-resistant pneumococci and meningococci. Further, some pneumococci are also chloramphenicol-resistant. This will undoubtedly affect the choice of antibiotics although the number of studies documenting a worsening clinical outcome is still small. In Europe and the USA third-generation cephalosporins have become first-line therapy but while these drugs remain relatively expensive, it is probably reasonable for most African hospitals to continue with the combination of a penicillin and chloramphenicol as initial therapy as long as clinicians are aware of the risk of recrudescence, particularly if steroids

A large number of clinical trials have been performed addressing the issue of whether steroids reduce the frequency of adverse outcomes, particularly hearing loss. It is not possible to discuss these studies in detail here, but certain points should be borne in mind when considering the evidence for and against steroids. Most trials could be criticized on methodological grounds because data were analysed without pre-defined end-points, allowing multiple comparisons to be made. In the three trials where significant results have been obtained, there were unusually high incidences of adverse outcome in the placebo group. Furthermore, no study with a consistent antibiotic regimen throughout has shown statistically significant reduction in hearing loss. Despite these problems, the case for giving dexamethasone in Hib meningitis is felt by many authorities to be strong. The role for dexamethasone in pneumococcal and meningococcal disease is at present

Many of the trials of both dexamethasone and antibiotic regimens have been performed in the United States, with Hib as the dominant aetiology and so considerable caution should be exercised when applying conclusion to the African setting A recent reported trial in Pakistan found no evidence that dexamethasone was beneficial and suggested that it may be

The finding of different outcomes in various settings is not uncommon. There are clearly huge differences in terms of population, genetics, and timing of presentation, microbiology and general supportive care which can explain this apparent discrepancy. Giving the added cost of dexamethasone to the family of a patient who has already begun receiving two antibiotics, we feel that there is insufficient evidence at this time to recommend routine use

WHO, in Africa, South of the Sahara which has all these facilities.

**7. Acute management**

are being used. Friedland 1998.

deleterious in this setting. Quazy (1996) Airede (2008)

of dexamethasone for acute bacterial meningitis of unknown cause.

unresolved.

The most common causes of bacterial Meningitis in the US, Europe and other developed countries since the 1980s have been the pneumococcus, Haemophilus influenza Type b, the meningococcus, Group B strepotococcus and Listeria monocytogenes.

Works on neonatal meningitis have also shown to involve Strept, agalaciac, Listeria monocytogene, and enteric gram neg. WAS E'coli and citrobacteria spp.Delourois (2009) Longe (1984) Laving (2003).

As already discussed under the epidemiology of meningitis in Africa, the three polysaccharide encapsulated bacteria most common in Ghana and Africa are Pheunococcus, Haemophilus influenza Type B and the Meningococcus.

The global epidemiology changed drastically during the 20th century as vaccines and antibiotics became available to prevent and treat the deadly disease.

Differential Diagonisis of Sensorineural Hearing loss in Ghanaian children revealed that, post-natal infections were the cause of about 60% of all Sensorineural Hearing loss in Ghanaian children, with measles leading with 30%, followed by malaria (Cerebral) with 14% and meningitis with 7.5%. See the Table Brobby (I986)11 (1986)1

Recent observations have revealed that Bacterial meningitis is on the increase threatening to overtake cerebral malaria.

This may be due to better management, and increased awareness and prevention of malaria in the sub region.

It is interesting to note that deafness as a medical and social problem in the third world shows itself not very much differently from the image it portrays itself in the developed countries. However, in the developed countries deafness as a handicap has been made visible and effectively treated and prevented.

For example, all childhood infections like Measles, Meningitis, Mumps and Malaria (the four MS) have been eliminated in the developed countries, by immunization.

The main cause of Deafness in US and Europe is due to otoseclerosis and chromosomal anomalies. For example while as connexin 26 mutation causes only 18% of Deafness in Ghana; it is responsible for causing 50% and more of Sensorineural Hearing loss in US and Europe. Brobby (1986)12 (1998)13 Hammelman et al (2001)14

It is important to observe that deafness remains a hidden handicap. In Africa delay in diagnosis is common because the vocalization of hearing impaired children parallels that of normal infants until the age of nine months; all children co and bubble; parents are indeed likely to assume that speech is developing normally, ignoring any subtle evidence of hearing impatient such as lack of response to environmental sounds.

The effect of deafness on a child is devastating. Ability to participate in school activities or in a community life at a level commensurate with others has been the comparative benchmark for quality of life across the millennia. Participation in the world be it modern or ancient, centres on communication. In ancient Greece, deafness represented a curse, an absence of intelligence, an inability to participate in community life. Throughout mediaval times the inability to understand or express speech meant that an individual was not allowed to inherit the family fortune. Being unable to speak, i.e. to communicate was not allowed to receive the sacraments of the Church, which reflected one of the primary elements of full participation in community life. It is therefore our duty as crusaders for the prevention of deafness to summon all efforts to encourage all Third World Countries to extend their programme of Immunization of the 6 killer diseases which have been eliminated in developed countries, Tuberculosis, Tetanus, Diphtheria, Pertusis, Measles and Poliomyelitis.

The various National Governments should be made aware that Measles, Meningitis, Mumps, Tetanus and Rubellen, can be effectively prevented by cheap, readily available and non-toxic immunization.

#### **9. Vaccination**

In many industrialized nations Hib has been virtually eliminated by the use of a conjugated vaccine. Before these results can be applied in Africa the epidemiology of Hib disease (uncertain because of technical problems with culture, especially in the face of pretreatment) must be characterized. A recent vaccine trial, in which Hib epidemiology in The Gambia was thoroughly assessed prior to the vaccination campaign, showed 95 per cent efficacy against invasive Hib disease and should serve as a model for future studies. Mulhdlland (1997)

At present, we are unaware of any African country which routinely vaccinates its children against Hib. Clearly, countries have many other health priorities, and the Hib vaccine is still relatively expensive although vaccination may actually be cost-effective in the long-term. Vaccination against group A and C meningococcal disease provides relatively short-lived immunity and has so far only been used to abort epidemics. Pneumococcal vaccine development has been hampered by the need to include a large number of serotypes.

#### **10. Rehabilitation**

Any sensorineural hearing loss is significant since even mild impairments may be of educational significance and subtle high-frequency deficits may interfere with the normal acquisition of language skills. Children with significant losses shuld be enrolled into a programme of rehabilitaition at a hearing assessment centre or a school for the deaf. Parental counselling is crucial for success. Most infants with even profound hearing loss retain some residual function, usually in the low frequencies. With early detection and management, this residual hearing can be harnessed by a comprehensive programme of amplification and auditory training (hearing aids and batteries should be commonplace commodities, affordable and available even in developing countries). This approach, in combination with simultaneous use of lip-reading and sign language, can transform the environment of a hearing-impaired child from a world of isolation, confusion and frustration to one of hope.

#### **11. References**

6 Meningitis

likely to assume that speech is developing normally, ignoring any subtle evidence of

The effect of deafness on a child is devastating. Ability to participate in school activities or in a community life at a level commensurate with others has been the comparative benchmark for quality of life across the millennia. Participation in the world be it modern or ancient, centres on communication. In ancient Greece, deafness represented a curse, an absence of intelligence, an inability to participate in community life. Throughout mediaval times the inability to understand or express speech meant that an individual was not allowed to inherit the family fortune. Being unable to speak, i.e. to communicate was not allowed to receive the sacraments of the Church, which reflected one of the primary elements of full participation in community life. It is therefore our duty as crusaders for the prevention of deafness to summon all efforts to encourage all Third World Countries to extend their programme of Immunization of the 6 killer diseases which have been eliminated in developed countries, Tuberculosis, Tetanus, Diphtheria, Pertusis, Measles

The various National Governments should be made aware that Measles, Meningitis, Mumps, Tetanus and Rubellen, can be effectively prevented by cheap, readily available and

In many industrialized nations Hib has been virtually eliminated by the use of a conjugated vaccine. Before these results can be applied in Africa the epidemiology of Hib disease (uncertain because of technical problems with culture, especially in the face of pretreatment) must be characterized. A recent vaccine trial, in which Hib epidemiology in The Gambia was thoroughly assessed prior to the vaccination campaign, showed 95 per cent efficacy against invasive Hib disease and should serve as a model for future studies.

At present, we are unaware of any African country which routinely vaccinates its children against Hib. Clearly, countries have many other health priorities, and the Hib vaccine is still relatively expensive although vaccination may actually be cost-effective in the long-term. Vaccination against group A and C meningococcal disease provides relatively short-lived immunity and has so far only been used to abort epidemics. Pneumococcal vaccine

Any sensorineural hearing loss is significant since even mild impairments may be of educational significance and subtle high-frequency deficits may interfere with the normal acquisition of language skills. Children with significant losses shuld be enrolled into a programme of rehabilitaition at a hearing assessment centre or a school for the deaf. Parental counselling is crucial for success. Most infants with even profound hearing loss retain some residual function, usually in the low frequencies. With early detection and management, this residual hearing can be harnessed by a comprehensive programme of

development has been hampered by the need to include a large number of serotypes.

hearing impatient such as lack of response to environmental sounds.

and Poliomyelitis.

**9. Vaccination**

Mulhdlland (1997)

**10. Rehabilitation**

non-toxic immunization.

[15] Mulholland K, Hilton S, Adegbila R, et al randomised trial of Hemophilus influenza type-b tetanus/protean conjugate for prevention pneumonia and menigitis in Gambian infants lancet 1997:349(9060) pp 1191-1197.

### **Emerging Pathogens in Neonatal Bacterial Meningitis**

Marisa Rosso, Pilar Rojas, Gemma Calderón and Antonio Pavón *UGC of Neonatology Hospital Virgen del Rocio, Spain*

#### **1. Introduction**

8 Meningitis

[15] Mulholland K, Hilton S, Adegbila R, et al randomised trial of Hemophilus influenza

Gambian infants lancet 1997:349(9060) pp 1191-1197.

type-b tetanus/protean conjugate for prevention pneumonia and menigitis in

Neonatal meningitis (NM) is a serious disease with substantial mortality and morbidity even among treated neonates (Overall, 1970; Harvey et al., 1999). Costs associated with treating false positive patients include prolonged hospital stay, exposure of the neonate to broad spectrum antibiotics, and insertion of central venous catheters for prolonged antibiotic administration.

The incidence of neonatal meningitis is difficult to accurately determine because of testing limitations. The incidence of bacterial meningitis is approximately 0.3 per 1000 live births in industrialized countries (Davies & Rudd, 1994). A recent study of neonatal infections in Asia (collecting data from China, Hong Kong, India, Iran, Kuwait, and Thailand), reported estimated incidence of neonatal meningitis from 0.48 per 1000 live births in Hong Kong to 2.4 per 1000 live births in Kuwait (Tiskumara et al., 2009). Another recent publication that looked at neonatal infections in Africa and South Asia found an incidence of neonatal meningitis ranging from 0.8 to 6.1 per 1000 live births (Thaver et al., 2009).

The rate of mortality from bacterial meningitis in developed countries among neonates has declined from almost 50% in the 1970s to less than 10% in the late 1990s due to advances in perinatal care over the last decades. However, a corresponding decrease in the morbidity rate has not occurred (Puopolo et al., 2005). Neonatal bacterial meningitis continues to be a serious disease with an unchanging rate of adverse outcome of 20-60%, despite a worldwide decline in mortality (Berardi et al., 2010). Morbidities related to neonatal bacterial meningitis continue to be a significant source of disability. In a prospective sample of more than 1500 neonates surviving until age 5 years, the prevalence of neuromotor disabilities including cerebral palsy was 8.1%, learning disability 7.5%, seizures 7.3%, and hearing problems 25.8%. No problems were reported in 65% of babies who survived group B streptococcal (GBS) meningitis and in 41.5% of those who survived *Escherichia coli (E.Coli)* meningitis (Bedford et al., 2001).

The three major pathogens in developed countries are: *Group B streptococcus*, gram negative rods and *Lysteria mococytogenes*. Group B streptococci are the most commonly identified organisms, implicated in roughly 50% of all cases of bacterial meningitis, and *E coli* accounts for another 20%; identification and treatment of maternal genitourinary infections is thus an important prevention strategy (Klinger et al., 2000). *Listeria monocytogenes* is the third most common pathogen, with 5-10% of cases; it is unique because it exhibits transplacental transmission (Heath et al., 2003). Historically regardless of the specific pathogen involved, neonatal meningitis is most often caused by vertical transmission during labor, but the increasing numbers of infants surviving premature delivery and advances in unit intensive care it is increasingly recognized as an emerging cause of hospital-acquired infection, particularly among severely debilitated or immunosuppressed patients. The accumulative incidence of meningitis is highest in the first month of life and is higher in preterm neonates than term neonates (Overall , 1970). For premature infants who develop meningitis, the neurodevelopmental consequences are often profound (Stoll et al., 2004). It occurs most frequently in the days following birth and is more common in premature infants than term infants (Davies & Rudd, 1994). Neonatal meningitis occurs in roughly 0.3 per 1000 live births; it is closely associated with sepsis, which is 5 times as common.

Risk factors for the development of meningitis include low birth weight (< 2500 g), preterm birth (< 37 weeks' gestation), premature rupture of membranes, traumatic delivery, fetal hypoxia, and maternal peripartum infection (including chorioamnionitis). Moreover neonates are at greater risk of sepsis and meningitis than other age groups because of deficiencies in humoral and cellular immunity and in phagocytic function. Infants younger than 32 weeks' gestation receive little of the maternal immunoglobulin received by full-term infants. (Volpe, 2008a,2008b). Inefficiency in the neonates alternative complement pathway compromises their defense against encapsulated bacteria (Krebs et al., 2007) T-cell defense and mediation of B-cell activity also are compromised. Finally, deficient migration and phagocytosis by neutrophils contribute to neonatal vulnerability to pathogens of even low virulence.

No one clinical sign is pathognomonic of meningitis. Because the signs of meningitis are subtle and nonspecific there may be delays in diagnosis and treatment (Feigin et al., 1992).

	- Symptoms appearing within the first 72 hours of life are referable primarily to systemic illness rather than meningitis. These include temperature inestability, episodes of apnea or bradycardia, hypotension, feeding difficulty, hepatic dysfunction, and irritability alternating with lethargy. (Volpe, 2008 a,2008b)
	- Respiratory symptoms can become prominent within hours of birth in GBS infection; however, the symptom complex also is seen with infection by *Escherichia coli* or *Listeria* species.
	- Late-onset bacterial meningitis (symptom onset beyond 72 hours of life) is more likely to be associated with neurologic symptoms. Most commonly seen are stupor and irritability, which Volpe describes in more than 75% of affected neonates.

Between 25% and 50% of neonates will exhibit the following neurological signs: seizures; bulging anterior fontanel; extensor posturing/ opisthotonus; focal cerebral signs including gaze deviation and hemiparesis; cranial nerve palsies. Nuchal rigidity per se is the least common neurologic sign in neonatal bacterial meningitis, occurring in fewer than 25% of affected neonates.

common pathogen, with 5-10% of cases; it is unique because it exhibits transplacental transmission (Heath et al., 2003). Historically regardless of the specific pathogen involved, neonatal meningitis is most often caused by vertical transmission during labor, but the increasing numbers of infants surviving premature delivery and advances in unit intensive care it is increasingly recognized as an emerging cause of hospital-acquired infection, particularly among severely debilitated or immunosuppressed patients. The accumulative incidence of meningitis is highest in the first month of life and is higher in preterm neonates than term neonates (Overall , 1970). For premature infants who develop meningitis, the neurodevelopmental consequences are often profound (Stoll et al., 2004). It occurs most frequently in the days following birth and is more common in premature infants than term infants (Davies & Rudd, 1994). Neonatal meningitis occurs in roughly 0.3 per 1000 live

Risk factors for the development of meningitis include low birth weight (< 2500 g), preterm birth (< 37 weeks' gestation), premature rupture of membranes, traumatic delivery, fetal hypoxia, and maternal peripartum infection (including chorioamnionitis). Moreover neonates are at greater risk of sepsis and meningitis than other age groups because of deficiencies in humoral and cellular immunity and in phagocytic function. Infants younger than 32 weeks' gestation receive little of the maternal immunoglobulin received by full-term infants. (Volpe, 2008a,2008b). Inefficiency in the neonates alternative complement pathway compromises their defense against encapsulated bacteria (Krebs et al., 2007) T-cell defense and mediation of B-cell activity also are compromised. Finally, deficient migration and phagocytosis by neutrophils contribute to neonatal vulnerability to pathogens of even low

No one clinical sign is pathognomonic of meningitis. Because the signs of meningitis are subtle and nonspecific there may be delays in diagnosis and treatment (Feigin et al., 1992).

 Symptoms appearing within the first 72 hours of life are referable primarily to systemic illness rather than meningitis. These include temperature inestability, episodes of apnea or bradycardia, hypotension, feeding difficulty, hepatic

 Late-onset bacterial meningitis (symptom onset beyond 72 hours of life) is more likely to be associated with neurologic symptoms. Most commonly seen are stupor and irritability, which Volpe describes in more than 75% of affected

Between 25% and 50% of neonates will exhibit the following neurological signs: seizures; bulging anterior fontanel; extensor posturing/ opisthotonus; focal cerebral signs including gaze deviation and hemiparesis; cranial nerve palsies. Nuchal rigidity per se is the least common neurologic sign in neonatal bacterial meningitis, occurring in fewer than 25% of

dysfunction, and irritability alternating with lethargy. (Volpe, 2008 a,2008b) Respiratory symptoms can become prominent within hours of birth in GBS infection; however, the symptom complex also is seen with infection by *Escherichia*

births; it is closely associated with sepsis, which is 5 times as common.

virulence.

Bacterial meningitis, early onset

*coli* or *Listeria* species.

Bacterial meningitis, late onset

neonates.

affected neonates.

Interpretation of cerebrospinal fluid (CSF) findings is more difficult in neonates than in older children, especially in premature infants whose more permeable blood-brain barrier causes higher levels of glucose and protein (Smith et al., 2008). So when faced with the need to make therapeutic decisions on the interpretation of CSF parameters, pediatricians, family practice physicians, and neonatologists often use The Harriet Lane Handbook as their guide (Robertson & Shilkofski, 2005). The classic finding of decreased CSF glucose, elevated CSF protein, and pleocytosis is seen more with gram-negative meningitis and with late grampositive meningitis; this combination also is suggestive of viral meningitis, especially HSV (Carges et al., 2006). The number of white blood cells found in the CSF in healthy neonates varies based on gestational age. Many authors use a cutoff of 20-30 WBC/µL. Only if all 3 parameters are normal does the lumbar puncture provide evidence against infection; no single CSF parameter exists that can reliably exclude the presence of meningitis in a neonate (Garges et al., 2006) .Bacterial meningitis commonly causes CSF pleocytosis greater than 100 WBC/µL, with predominantly polymorphonuclear leukocytes gradually evolving to lymphocytes (Garges et al., 2006).

Emerging pathogens are those that have appeared in a human population for the first time, or have occurred previously but are increasing in incidence or expanding into areas where they have not previously been reported, usually over the last 20 years (World Health Organization (WHO), 1997). In our patients, the reported risk factors associated with emerging pathogens infection are prematurity, neurosurgical procedures (especially shunts and drainages), intracranial haemorrhages. Our current patients have been undergone several neurosurgical procedures and also, importantly, have been treated with a previous broad-spectrum antibiotic, which is also a suggested risk factor for infection with these emerging pathogens (*Stenotrophomonas Maltophilia (*Rojas et al., 2009)*, Kluyvera ascorbata (*Rosso et al., 2007), *Enterobacter sakazakii (*Hunter et al., 2008) and *Rhodococcus equi (*Strunk et al., 2007)*.* Although these pathogens are considered an infrequent cause of meningitis, it has become a focus of interest not only due to increasing recognition of its pathogenic potential but also because of its marked antibiotic resistance*.*

#### **2. Emerging pathogens and clinical case reports**

In this chapter we report several cases of these emerging pathogens meningitis in newborns successfully treated. Two of them have been reported previously for us.

#### **2.1 Rhodococcus equi (R. equi)**

R*hodococcus equi* is a Gram-positive, aerobic, pleomorphic, nonmotile, branching filamentous coccobacillus and was first isolated from the lungs of foals in Sweden in 1923 by Magnusson. Called *Rhodococcus* because of its ability to form a red (or salmon-colored) pigment, *R. equi* can be weakly acid-fast and bears a similarity to diphtheroids. *R. equi*  primarily causes zoonotic infections that affect grazing animals. The first report of human infection occurred in the 1960s.The natural reservoir for this organism appears to be soil. The two main methods of acquiring this organism are inhalation and direct inoculation through trauma. Infections with *R. equi* have a significant potential for hematogenous dissemination, with bacteremia occurring in up to 80% of immunocompromised patients (Emmons et al., 1991).

#### **2.1.1 Case report**

Patient was born as the first of twin brothers at 27 +2 weeks. The pregnancy was complicated by twintwin-transfusion syndrome, with twin 1 being the recipient. Delivery was by cesarean section for fetal distress. The APGAR scores at 1 and 5 minutes were 8 and 9, respectively. Shortly after delivery, the baby developed respiratory distress syndrome requiring intubation and ventilation for 2 days. After that, respiratory support was by continuous positive airway pressure. On day 10, sepsis with coagulase-negative staphylococci was treated with intravenous vancomycin (10 days) and gentamicin (3 days). Head ultrasound examination on day 1 was normal, but a repeated scan on day 7 revealed a right-sided grade III intraventricular hemorrhage. Subsequent examinations demonstrated a slow increase of the size of the lateral ventricles and elevated resistive indices indicative of posthemorrhagic hydrocephalus. Therapeutic lumbar punctures performed 2–3 times per week yielded sterile cerebrospinal fluid (CSF). Cerebral magnetic resonance imaging on day 57 demonstrated post hemorrhagic aqueduct stenosis with dilated lateral and third ventricles. A ventriculoperitoneal-shunt was inserted on day 59 under perioperative antibiotic prophylaxis with intravenous vancomycin (1 dose) and cefotaxime (3 doses). On day 61, the baby developed apnea episodes and seizures requiring intubation and mechanical ventilation. A lumbar puncture was performed and CSF showed 24 106/L white cells (56% neutrophils) and 56 106/L erythrocytes. Gram-positive bacilli were seen in the CSF. Empiric antibiotic treatment with intravenous vancomycin (15 mg/kg/dose twice daily), meropenem (40 mg/kg/dose thrice daily), and ciprofloxacin (10 mg/kg/dose twice daily) was started. The VP-shunt was externalized on day 63 and removed on day 67. Cultures of the removed shunt and follow-up lumbar puncture CSF did not grow bacteria. The initial CSF culture had bacterial growth on day 68. CSF plated onto Blood Agar (Columbia agar base, Oxoid, Melbourne, Australia) and Chocolate Agar (GC agar base, Oxoid) and incubated at 35°C in a 5% CO2 atmosphere for 48 hours grew colonies 3–4 mm in diameter, irregularly round, smooth, and semitransparent. Production of salmon-colored pigmentation occurred after 4 days incubation. Gram stain revealed the presence of irregular shaped Gram-positive bacilli. Colonies were catalase- positive, oxidase negative, nitrate reduction positive, alkaline phosphatase positive, and urease negative. By the API Coryne system (Biomerieux, Marcyl'Etoile, France), the profile number was 1100004. The organism produced equi factors that interacted with the beta-toxin of *Staphylococcus aureus*  to give an area of complete hemolysis on Sheep Blood Agar (Trypticase Soy agar base, Oxoid). Identification of *Rhodococcus equi* was confirmed by cellular fatty acid analysis and DNA sequencing. The antibiotic regimen was changed to intravenous vancomycin (15 mg/kg/dose twice daily) and rifampin (20 mg/kg once daily) and continued until day 90. This was followed by oral treatment with rifampin (10 mg/kg once daily) and azithromycin (10 mg/kg once daily) for a further 3 months. The baby's condition improved, and the CSF white cell count normalized. At the chronologic age of 6.5 months, a VP-shunt was reinserted without complications because of increasing hydrocephalus. When last seen at corrected age of 1 year, the boy had made good developmental progress with only slightly delayed motor skills.

#### **2.2 Kluyvera ascorbata (K. ascorbata)**

A new genus in the family *Enterobacteriaceae* in 1981 using molecular characterization and deoxyribonucleic acid (DNA)-DNA hybridation techniques. Strains of *Kluyvera* were divided into two named species, *Kluyvera ascorbata* and *Kluyvera cryocrescens,* and a third unnamed group, *Kluyvera* species group 3 (Farmer et al., 1981). The genus currently consists of 4 species, *K. ascorbata*, *K. cryocrescens, K. georgina* (formerly species group 3) and *K.cochleae (*Carter et al., 2005). It is a small, motile Gram-negative bacillus with peritrichous flagella that is oxidase- negative and catalase- positive, and it ferments glucose (Farmer et al., 1981; Brooks et al., 2003; Narchi et al., 2005; Paredes-Rodriguez et al., 2002). Confirmatory species identification of *Kluyvera* requires the demonstration of ascorbate utilization and glucose fermentation at 5ºC*. Kluyvera* is present in the environment in water, soil, sewage, hospital sinks, and food products of animal origin (Brooks et al., 2003). It also has been isolated from a variety of human specimens (most commonly sputum, urine, stool, throat, and blood).It was initially considered to be a benign saprophyte predominantly colonizing the respiratory, gastrointestinal or urinary tract (Carter et al., 2005; Narchi et al., 2005;Sarria et al., 2001).

#### **2.2.1 Case report**

12 Meningitis

Patient was born as the first of twin brothers at 27 +2 weeks. The pregnancy was complicated by twintwin-transfusion syndrome, with twin 1 being the recipient. Delivery was by cesarean section for fetal distress. The APGAR scores at 1 and 5 minutes were 8 and 9, respectively. Shortly after delivery, the baby developed respiratory distress syndrome requiring intubation and ventilation for 2 days. After that, respiratory support was by continuous positive airway pressure. On day 10, sepsis with coagulase-negative staphylococci was treated with intravenous vancomycin (10 days) and gentamicin (3 days). Head ultrasound examination on day 1 was normal, but a repeated scan on day 7 revealed a right-sided grade III intraventricular hemorrhage. Subsequent examinations demonstrated a slow increase of the size of the lateral ventricles and elevated resistive indices indicative of posthemorrhagic hydrocephalus. Therapeutic lumbar punctures performed 2–3 times per week yielded sterile cerebrospinal fluid (CSF). Cerebral magnetic resonance imaging on day 57 demonstrated post hemorrhagic aqueduct stenosis with dilated lateral and third ventricles. A ventriculoperitoneal-shunt was inserted on day 59 under perioperative antibiotic prophylaxis with intravenous vancomycin (1 dose) and cefotaxime (3 doses). On day 61, the baby developed apnea episodes and seizures requiring intubation and mechanical ventilation. A lumbar puncture was performed and CSF showed 24 106/L white cells (56% neutrophils) and 56 106/L erythrocytes. Gram-positive bacilli were seen in the CSF. Empiric antibiotic treatment with intravenous vancomycin (15 mg/kg/dose twice daily), meropenem (40 mg/kg/dose thrice daily), and ciprofloxacin (10 mg/kg/dose twice daily) was started. The VP-shunt was externalized on day 63 and removed on day 67. Cultures of the removed shunt and follow-up lumbar puncture CSF did not grow bacteria. The initial CSF culture had bacterial growth on day 68. CSF plated onto Blood Agar (Columbia agar base, Oxoid, Melbourne, Australia) and Chocolate Agar (GC agar base, Oxoid) and incubated at 35°C in a 5% CO2 atmosphere for 48 hours grew colonies 3–4 mm in diameter, irregularly round, smooth, and semitransparent. Production of salmon-colored pigmentation occurred after 4 days incubation. Gram stain revealed the presence of irregular shaped Gram-positive bacilli. Colonies were catalase- positive, oxidase negative, nitrate reduction positive, alkaline phosphatase positive, and urease negative. By the API Coryne system (Biomerieux, Marcyl'Etoile, France), the profile number was 1100004. The organism produced equi factors that interacted with the beta-toxin of *Staphylococcus aureus*  to give an area of complete hemolysis on Sheep Blood Agar (Trypticase Soy agar base, Oxoid). Identification of *Rhodococcus equi* was confirmed by cellular fatty acid analysis and DNA sequencing. The antibiotic regimen was changed to intravenous vancomycin (15 mg/kg/dose twice daily) and rifampin (20 mg/kg once daily) and continued until day 90. This was followed by oral treatment with rifampin (10 mg/kg once daily) and azithromycin (10 mg/kg once daily) for a further 3 months. The baby's condition improved, and the CSF white cell count normalized. At the chronologic age of 6.5 months, a VP-shunt was reinserted without complications because of increasing hydrocephalus. When last seen at corrected age of 1 year, the boy had made good developmental progress with only slightly

A new genus in the family *Enterobacteriaceae* in 1981 using molecular characterization and deoxyribonucleic acid (DNA)-DNA hybridation techniques.  The herniation was reduced and the defect repaired and a ventriculoperitoneal shunt was inserted. Five days following surgery he development fever, irritable crying and poor appetite. The physical examination was otherwise normal. Blood tests showed a peripheral white blood cell count of 4x109 /L, normal hemoglobin and platelet count and a C-reactive protein of 148 mg/L. Urine analysis by the dipstick method was normal. Cerebrospinal fluid obtained by ventriculoperitoneal shunt puncture was yellow and turbid. Analysis of CSF revealed pleocytosis with a white blood cell count of 11664 cells/mm3 (98% neutrophils), protein 3.4 g/l, glucose 0.01 g/l. The concomitant plasma glucose was normal. Blood, urine and CSF cultures were obtained. The Gram stain of CSF was negative. Empirical antibiotic therapy with meropenem was started. Blood and urine cultures were normal. *Kluyvera ascorbata* was isolated from CSF sample. It was susceptible in vitro to third generation cephalosporins, trimethoprim, aminoglycosides, aztreonam, fluorquinolones, imipenem and amoxicillin-clavulanate; it was resistant to first generation cephalosporins and with intermediate susceptibility to second generation cephalosporins. Despite treatment with antibiotics, the patient remained febrile and with poor appetite. A computed tomography brain scan showed a left dilated ventricle. The shunt was removed and a temporary external CSF drainage was inserted. Two days after external CSF drainage was inserted, he became afebrile and appeared better. CSF analyses performed after 21 days of treatment revealed clear CSF. There were no white blood cells and the protein and glucose values were 2.7 g/l and 0.34 g/l, respectively. Gram stain of that CSF specimen failed to reveal bacteria and the culture was sterile. He received antibiotic therapy for 28 days, a ventriculoperitoneal shunt was replaced after infection was eradicated.

#### **2.3 Stenotrophomonas maltophilia (S. maltophilia)**

Is a nonfermentative Gram-negative bacillus, previously known as *Pseudomonas maltophilia* and later *Xanthomonas maltophilia*. This bacterium is found in several environments such as water, soil, plants, food and hospital settings (Nicodemo & Garcia –Paez 2007; Yemisen et al., 2008). It is increasingly recognised as a significant cause of hospital acquired infection particularly among severely debilitated and immunosuppressed patients, those receiving longterm antimicrobial therapy and those with indwelling central venous catheters. The resultant infections are extensive, with the respiratory tract, soft tissues and the skin most frequently involved (Nicodemo & Garcia –Paez 2007; Denis et al., 1977).

#### **2.3.1 Case report**

A baby boy was delivered at 26 weeks of gestation after a spontaneous rupture of membranes. The patient was admitted to our neonatal intensive care unit with Apgar scores of two and eight at 1 and 5 minutes, respectively. On the 12th day of his life clinical and radiological signs of perforated necrotizing enterocolitis (NEC) occurred and required surgical intestinal resection. Cerebral ultrasound at day 15 of his life was performed and showed intraventricular haemorrhage and dilated cerebral ventricles. Because of NEC, temporary external CSF drainage was inserted. Two weeks after external CSF drainage was performed, he developed *Klebsiella Extended-spectrum beta-lactamase (ESBL)* meningitis. Antibiotic therapy with meropenem was started and the external CSF drainage was replaced. After 19 days of treatment with meropenem a new CSF sample from drainage revealed 1200 cells/mm3 (95% neutrophils), protein 3.4 g/L and glucose 0.03 g/L. Gramnegative bacillus were seen on gram strain in the CSF culture and it was positive for *S. maltophilia.* The strain was only susceptible in vitro to trimethoprimsulfamethoxazole (TMP-SMX), with a mean inhibitory concentration (MIC) of ≤2/38, minocycline and ciprofloxacin. TMP-SMX intravenous therapy (50 mg/kg per day in two divided doses) was commenced. The external ventricular drainage was not removed at this stage because the patient's state was critical. The next sample analysis of CSF from the drainage 14 days after starting TMP-SMX revealed the following profile: white blood cell count of 1300 cells/mm3 (90% neutrophils), protein 1.39 g/L and glucose 0.04 g/L. The CSF culture was still positive for *S. maltophilia* and consequently ciprofloxacin (15 mg/kg per day in two divided doses) was added to TMP-SMX. Furthermore, the external ventricular drainage was removed and after 7 days of therapy with ciprofloxacin in combination with TMP-SMX, the analysis of the CSF was normal and the culture was sterile. Finally, 21 more days of therapy were completed with both antibiotics. No adverse effects were found during ciprofloxacin treatment. There was no displacement of bilirubin with the use of sulfamethoxazole in our patient and the values were normal (maximum total bilirubin 127 mg/dL). A ventricular-peritoneal shunt was inserted after the infection was eradicated due to severe ventricular dilatation.

#### **2.4 Enterobacter sakazakii (E. sakazakii)**

Is a motile, non-sporeforming, Gramnegative facultative anaerobe. It was known as 'yellow pigmented Enterobacter cloacae' until 1980 when it was designated as a new species by Farmer, Asbury, Hickman and Brenner in honour of the Japanese bacteriologist Riichi Sakazaki. They reported that DNA–DNA hybridization studies found no clear generic assignment for *E. sakazakii* as it was 53–54% related to Enterobacter and *Citrobacter* species. A comparison of the type strains of these two genera showed that E. sakazakii was 41% related to *C. freundii* and 51% related to *E. cloacae*. Subsequently, since it was also phenotypically closer to E. cloacae, Farmer, Asbury, Hickman and Brenner (1980) assigned the organism to the *Enterobacter* genus.The natural habitat of *E. sakazakii* is unknown, but it has been isolated from a number of hospital sources (Farmer et al., 1980). Most of these reports describe single cases. Because pigment production, a distinguishing characteristic of *E. sakazakii*, is greatly diminished at the usual incubation temperature of 36°C, it seemed likely that a number of *E. sakazakii* isolates were not recognized as atypical *E. cloacae* in the past

#### **2.4.1 Cases report**

14 Meningitis

particularly among severely debilitated and immunosuppressed patients, those receiving longterm antimicrobial therapy and those with indwelling central venous catheters. The resultant infections are extensive, with the respiratory tract, soft tissues and the skin most

A baby boy was delivered at 26 weeks of gestation after a spontaneous rupture of membranes. The patient was admitted to our neonatal intensive care unit with Apgar scores of two and eight at 1 and 5 minutes, respectively. On the 12th day of his life clinical and radiological signs of perforated necrotizing enterocolitis (NEC) occurred and required surgical intestinal resection. Cerebral ultrasound at day 15 of his life was performed and showed intraventricular haemorrhage and dilated cerebral ventricles. Because of NEC, temporary external CSF drainage was inserted. Two weeks after external CSF drainage was performed, he developed *Klebsiella Extended-spectrum beta-lactamase (ESBL)* meningitis. Antibiotic therapy with meropenem was started and the external CSF drainage was replaced. After 19 days of treatment with meropenem a new CSF sample from drainage revealed 1200 cells/mm3 (95% neutrophils), protein 3.4 g/L and glucose 0.03 g/L. Gramnegative bacillus were seen on gram strain in the CSF culture and it was positive for *S. maltophilia.* The strain was only susceptible in vitro to trimethoprimsulfamethoxazole (TMP-SMX), with a mean inhibitory concentration (MIC) of ≤2/38, minocycline and ciprofloxacin. TMP-SMX intravenous therapy (50 mg/kg per day in two divided doses) was commenced. The external ventricular drainage was not removed at this stage because the patient's state was critical. The next sample analysis of CSF from the drainage 14 days after starting TMP-SMX revealed the following profile: white blood cell count of 1300 cells/mm3 (90% neutrophils), protein 1.39 g/L and glucose 0.04 g/L. The CSF culture was still positive for *S. maltophilia* and consequently ciprofloxacin (15 mg/kg per day in two divided doses) was added to TMP-SMX. Furthermore, the external ventricular drainage was removed and after 7 days of therapy with ciprofloxacin in combination with TMP-SMX, the analysis of the CSF was normal and the culture was sterile. Finally, 21 more days of therapy were completed with both antibiotics. No adverse effects were found during ciprofloxacin treatment. There was no displacement of bilirubin with the use of sulfamethoxazole in our patient and the values were normal (maximum total bilirubin 127 mg/dL). A ventricular-peritoneal shunt

was inserted after the infection was eradicated due to severe ventricular dilatation.

Is a motile, non-sporeforming, Gramnegative facultative anaerobe. It was known as 'yellow pigmented Enterobacter cloacae' until 1980 when it was designated as a new species by Farmer, Asbury, Hickman and Brenner in honour of the Japanese bacteriologist Riichi Sakazaki. They reported that DNA–DNA hybridization studies found no clear generic assignment for *E. sakazakii* as it was 53–54% related to Enterobacter and *Citrobacter* species. A comparison of the type strains of these two genera showed that E. sakazakii was 41% related to *C. freundii* and 51% related to *E. cloacae*. Subsequently, since it was also phenotypically closer to E. cloacae, Farmer, Asbury, Hickman and Brenner (1980) assigned the organism to the *Enterobacter* genus.The natural habitat of *E. sakazakii* is unknown, but it has been isolated from a number of hospital sources (Farmer et al., 1980). Most of these reports describe single

**2.4 Enterobacter sakazakii (E. sakazakii)**

frequently involved (Nicodemo & Garcia –Paez 2007; Denis et al., 1977).

**2.3.1 Case report**

Infection of the newborn is probably through ingestion of contaminated infant milk formula and not through vertical transmission from the mother during birth (Mutyjens & Kollee, 1990). The first reported association of *E. sakazakii* with contaminated Infant milk formula (IMF) powder was by (Muytjens et al., 1983) in the Netherlands studying eight cases of neonatal meningitis and sepsis. *E. sakazakii* was isolated from prepared milk formula, a dish brush and a stirring spoon. These isolateswere studied in more detail later by( Smeets et al., 1998). In Iceland three cases were reported linked to milk formula contaminated with *E. sakazakii* (Biering et al., 1989). US Centers for Disease Control and Prevention (Himelright et al., 2002) reported an investigation into the 2001 Tennessee outbreak of *E. sakazakii* in a neonatal intensive care unit in which 10 cases were identified. The index case was a male infant (born at 33.5 weeks) who had been admitted to the neonatal intensive care unit because of premature birth weight and respiratory distress. After 11 days the baby developed symptoms of meningitis (fever, tachycardia, decreased vascular perfusions and suspected seizure activity) and despite being given intravenous antibiotics the infant died after a further 9 days. *E. sakazakii* was cultured from the cerebrospinal fluid. Following increased surveillance a further 10 cases of *E. sakazakii* colonisation were found on the neonatal unit; 2 from 'nonsterile' site with clinical deterioration. The use of infant formula milk was the only factor associating the cases. More recently (Simon et al., 2010) described a case of meningitis in a neonatal intensive care unit occurred as a result of the use of a powered infant formula contaminated with *E. sakazakii* at manufacturing level, and an inadequate preparation and storing of the reconstituted product were identified as risk factors.

#### **3. Discussion**

The potential virulence of these pathogens above mentioned have been uncertain in the past, owing in part to its relatively recent characterization and the small number of reported clinical infections.

The reported risk factors associated with these pathogens infection are prematurity, neurosurgical procedures (especially shunts and drainages), intracranial haemorrhages and malignancies (Caylan et al., 2002). Our patients had undergone several neurosurgical procedures and also importantly, had been treated with a previous broad-spectrum antibiotic such as ampicillin, 3rd generation cephalosporins and carbapenem, which is also a suggested risk factor for infection. Aggressive antimicrobial intervention is lifesaving in neonates with suspected meningitis.

These emergent pathogens are increasingly recognised as a cause of nosocomial infections of special interest because of its intrinsic resistance to multiple antimicrobial agents used to treat Gram-negative infections. So (Rojas et al., 2009) found *S. maltophilia* isolates were resistant to ampicillin, cefazolin and extended spectrum penicillins, but were susceptible to the aminoglycosides and trimethoprimsulfamethoxazole. It is resistant to a variety of antibiotics, for example aminoglycosides, ß-lactam agents and it is intrinsically resistant to carbapenems. Based on susceptibility studies, TMP-SMX is the drug of choice for treatment of *S. maltophilia* infections. However, recent data indicate that the percentage of strains resistant to TMPSMX may be increasing(Nicodemo & Garcia –Paez 2007; Wen-Tsung et al., 2002; Krcmery V et al., 1999; Van den Oever et al., 1998). In this patient the pathogen was susceptible to this antimicrobial therapy but CSF cultures only became sterile after removal of the external ventricular drainage and the addition of ciprofloxacin to TMP-SMX. We decided to add ciprofloxacin because TMP-SMX is bacteriostatic and the infant was seriously ill (Table1). The administration of sulfamethoxazole, which binds to albumin and competes with bilirubin, can increase the possibility of hyperbilirubinaemia and serious neurological complications such as kernicterus in neonates. This was not observed in our patient.

Little information is available regarding the in vitro antibiotic susceptibilities and clinical effectiveness of antibiotics in *Kluyvera* infections. The agents most consistently active in vitro against *Kluyvera* are third-generation cephalosporins, fluorquinolones, aminoglycosides, imipenem, chloramphenicol, and nitrofurantoin. Most strains are resistant to ampicillin, first and second-generation cephalosporins and ticarcillin. Agents with variable activity include ampicillin-sulbactam, aztreonam, piperacillin, tetracycline and trimethoprimsulfamethoxazole. (Narchi et al., 2003; Sarria et al.,2001). In our case, above mentioned the *Kluyvera* species was also sensitive to third-generation cephalosporins, quinolones, aminoglycosides and carbapenems. We used meropenem with a good clinical response. We used this antibiotic because of predisposing factors for resistant hospital acquired microorganisms such as colonization with nosocomial pathogens, broad spectrum antibiotic usage, underlying disease and intensive care unit admission.

(Lai, 2001) found all *E. sakazakii* isolates were resistant to ampicillin, cefazolin and extended spectrum penicillins, but were susceptible to the aminoglycosides and trimethoprimsulfamethoxazole. Whereas sensitivity to 3rd generation cephalosporins and the quinolones was variable. Subsequently (Lai, 2001) proposed the use of carbapenems or 3rd generation cephalosporins with an aminoglycoside or trimethoprim with sulfamethoxazole. This treatment regime has improved the outcome of E. sakazakii meningitis though the resistanceof *Enterobacter spp*. to these antibiotics is increasing (Lai, 2001; Dennison & Morris, 2002) have reported an *E. sakazakii* infection that was resistant to multiple antibiotics, including ampicillin, gentamicin and cefotaxamine.

Other hand selection of antibiotics should be determined based on likely pathogen, local patterns of antibacterial drug sensitivities, and hospital policies. When NM is suspected, treatment must be aggressive, as the goal is to achieve bactericidal concentration of antibiotics and to sterilize CSF as soon as possible with empiric antibiotic treatment should include agents active against all main pathogens; but we must be alert because these novel pathogens are resistant to a variety of antibiotics, for example aminoglycosides, ß-lactam agents and including to carbapenems. Here, we have reported our experience with these emerging pathogens in neonatal meningitis.

#### **4. Conclusion**

16 Meningitis

carbapenems. Based on susceptibility studies, TMP-SMX is the drug of choice for treatment of *S. maltophilia* infections. However, recent data indicate that the percentage of strains resistant to TMPSMX may be increasing(Nicodemo & Garcia –Paez 2007; Wen-Tsung et al., 2002; Krcmery V et al., 1999; Van den Oever et al., 1998). In this patient the pathogen was susceptible to this antimicrobial therapy but CSF cultures only became sterile after removal of the external ventricular drainage and the addition of ciprofloxacin to TMP-SMX. We decided to add ciprofloxacin because TMP-SMX is bacteriostatic and the infant was seriously ill (Table1). The administration of sulfamethoxazole, which binds to albumin and competes with bilirubin, can increase the possibility of hyperbilirubinaemia and serious neurological complications such as kernicterus in neonates. This was not

Little information is available regarding the in vitro antibiotic susceptibilities and clinical effectiveness of antibiotics in *Kluyvera* infections. The agents most consistently active in vitro against *Kluyvera* are third-generation cephalosporins, fluorquinolones, aminoglycosides, imipenem, chloramphenicol, and nitrofurantoin. Most strains are resistant to ampicillin, first and second-generation cephalosporins and ticarcillin. Agents with variable activity include ampicillin-sulbactam, aztreonam, piperacillin, tetracycline and trimethoprimsulfamethoxazole. (Narchi et al., 2003; Sarria et al.,2001). In our case, above mentioned the *Kluyvera* species was also sensitive to third-generation cephalosporins, quinolones, aminoglycosides and carbapenems. We used meropenem with a good clinical response. We used this antibiotic because of predisposing factors for resistant hospital acquired microorganisms such as colonization with nosocomial pathogens, broad spectrum antibiotic

procedure Therapy Outcome

TMP-SMX,

sulphadoxine Recovered

ciprofloxacin Recovered

usage, underlying disease and intensive care unit admission.

Year Age/sex Neurosurgical

Table 1. Details of children with meningitis caused by *S. maltophilia*

multiple antibiotics, including ampicillin, gentamicin and cefotaxamine.

1 1977 8 months/male None Ampicilin, colistin Died

female None Chloramphenicol,

External (CSF) drainage

(Lai, 2001) found all *E. sakazakii* isolates were resistant to ampicillin, cefazolin and extended spectrum penicillins, but were susceptible to the aminoglycosides and trimethoprimsulfamethoxazole. Whereas sensitivity to 3rd generation cephalosporins and the quinolones was variable. Subsequently (Lai, 2001) proposed the use of carbapenems or 3rd generation cephalosporins with an aminoglycoside or trimethoprim with sulfamethoxazole. This treatment regime has improved the outcome of E. sakazakii meningitis though the resistanceof *Enterobacter spp*. to these antibiotics is increasing (Lai, 2001; Dennison & Morris, 2002) have reported an *E. sakazakii* infection that was resistant to

male None None Died

female None Ciprofloxacin Recovered

observed in our patient.

Reference/

2 1977 13 months/

3 1984 7 days/

4 2002 4 days/

5 2009 69 days/

male

Case No

In summary we are witnessing new emerging pathogens causing potentially fatal bacterial neonatal meningitis. Here, we report our experience with these emerging pathogens. Given the expected increase in the future regarding the frequency of these emerging pathogens causing nosocomial infections including meningitis due to these organisms in neurosurgical patients and its marked resistance to antibiotics, they should be considered as a potential cause of meningitis in neonates with external ventricular drainage who are receiving long term broad spectrum antimicrobial therapy.

#### **5. Acknowledgements**

We would like to express our gratitude to Dr. Olaf Neth for technical support.

#### **6. References**

Denis, F.; Sow, A. & David M. (1977).Etude de deux cas de meningitis a Pseudomonas maltophilia observes au Senegal. *Bull Soc Med Afr Noire Lang Fr,* Vol. 22, pp.135-9. Emmons, W.; Reichwein, B. & Winslow, DL (1991). *Rhodococcus equi* infection in the patient

Farmer, JJ III.; Asbury, MA.; Hickmann, FW. & Brenner, DJ. (1980). *Enterobacter sakazakii*: a

Farmer, JJ III.; Fanning, GR.; Huntley-Carter, GP.; Holmes, B., Hickman, FW.; Richard, C. &

Garges, HP.; Moody, MA.; Cotten, CM.; Smith, PB.; Tiffany, KF.; Lenfestey, R.; Li, JS.;

Heath, PT.; Nik Yusoff, NK. & Baker, CJ.(2003). Neonatal meningitis. *Arch Dis Child Fetal*

Himelright, I.; Harris, E.; Lorch, V.; Anderson, M.; Jones, T.; Craig; A.; Kuehnert, M.; Forster,

Iversen, C. S & Forsythe, J. (2003). Risk profile of *Enterobacter sakazakii*, an emergent

Klinger, G.; Chin, CN.; Beyene, J. & Perlman, N.(2000). Predicting the outcome of neonatal

Krcmery, V Jr.; Filka, J.; Uher, J.; Kurak, H.; Sagat, T.; Tuharsky, J.; Novak, I.; Urbanova, T.;

Krebs, VLJ. & Costa GAM. (2007). Clinical outcome of neonatal bacterial meningitis

Lai KK.(2001). Enterobacter sakazakii infections among neonates, infants, children, and adults: Case reports and a review of the literature. *Medicine,* Vol.80, pp.113–122 Magnusson, H(1923). Spezifische infektio¨se Pneumonie beim Fohlen: ein neuer Eitererreger

Muytjens, HL.; Zanen, HC.; Sonderkamp, HJ.; Kollee, LA.; Wachsmuth, IK. & Farmer,

Muytjens, HL. & Kolee, LA. (1990). Enterobacter sakazakii meningitis in neonates: causative

JJ.III.(1983) Analysis of eight cases of neonatal meningitis and sepsis due to

according to birth weight. *Arq,* December; Vol.65, pp.1149-1153.

beim Pferd. *Arch Wiss Prakt Tierheilkd,* Vol.50, pp.22–38

Enterobacter sakazakii. *J Clin Microbiol,* Vol.18, pp.115–120

role of formula?. *Pediatric Infectious Disease*, Vol.9, pp. 372–73.

pp.91–6.

443-54

pp.75-80.

*Bacteriol,* Vol.30, pp.569-84.

meningitis. *Pediatr Infect Dis J,* Vol.11, pp.785–814

parameters?. *Pediatrics,* Apr; Vol. 117(4), pp. 1094-100

bacterial meningitis. *Pediatrics,* Sep Vol.106(3), pp.477-82

*Neonatal Ed*. May, Vol.88(3), pp.F173-8.

*Mortality Weekly Report*, Vol.51, pp. 298–300.

with AIDS: literature review and report of an unusual case. *Rev Infect Dis,* Vol.13,

new species of "*Enterobacteriaceae*" isolated from clinical specimens. *Int. J. Syst.*

Brener, DJ. (1981) *Kluyvera*, a new (redefined) genus in the family Enterobacteriaceae: identification of *Kluyvera ascorbata* sp. nov. and *Kluyvera cryocrescens* sp. nov. in clinical specimens. *J Clin Microbiol,* Vol. 13, pp.919-933 Feigin, RD.; McCracken, GH Jr. & Klein, JO.(1992). Diagnosis and management of

Fowler, VG. & Benjamin, DK Jr.(2006). Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid

T.; Arduino, M.; Jensen, B. & Jernigan, D.(2002). Enterobacter sakazakii infections associated with the use of powdered infant formula — Tennessee, 2001. *Morbidity*

pathogen associated with infant milk formula.*Trends Food Sci.Technol,* Vol.11, pp.

Kralinsky, K.; Mateicka, F.;, Krcméryová, T.; Jurga, L.; Sulcová, M.; Stencl, J. & Krúpová, I.(1999) Ciprofloxacin in treatment of nosocomial meningitis in neonates and in infants: report of 12 cases and review. *Diagn Microbiol Infect disease,* Vol.35,

### **Perspectives of Neonatal-Perinatal Bacterial Meningitis**

Kareem Airede *University of Abuja Nigeria*

#### **1. Introduction**

20 Meningitis

Volpe JJ(2008b). Bacterial and fungal intracranial infections. In: *Neurology of the Newborn*. 5th.

Volpe JJ. (2008a).Viral, protozoal, and related intracranial infections. In: *Neurology of the*

Wen-Tsung, L.; Chin-Chien, W.; Chuen-Ming, L. & Mong-Ling, C.(2002) Successful

Yemisen, M.; Mete, B.; Tunali, Y.; Yentur, E. & Ozturk, R.(2008). A meningitis case due to

treatment of multi-resistant Stenotrophomonas maltophilia meningitis with

Stenotrophomonas maltophilia and review of the literature. *Int J Infect Dis,* Vol. 23,

*Newborn*. 5th. Philadelphia, Pa: Saunders Elsevier, pp.851-915.

ciprofloxacin in a pre-term infant. *Eur J Pediatr,* Vol.161, pp.680-2.

Philadelphia, Pa: Saunders Elsevier, pp.916-56.

pp.1-3.

Bacterial meningitis is generally a devastating infection of the leptomeninges and underlying subarachnoid cerebrospinal fluid with a high mortality rate, particularly in the perinatal and neonatal infant. This is more worrisome because despite the more available potent antimicrobials and variably effective vaccines, the disease remains a significant cause of morbidity and mortality. Mortality rates could be as high as between 25 - 50% depending on which series as well as the area of practice, whilst morbidity, often neurologic, could be as elevated as 25 – 45%.

Many clinical and etiologic studies performed over the recent decades have demonstrated that different species of bacteria can precipitate Neonatal-Perinatal bacterial meningitis. *Streptococcus agalactiae, Staphyloccocus aureus,* Group B *β-Haemolytic streptococci* [GBS], Gramnegative bacilli, *Haemophilus influenzae* type *b*, *Neisseria meningitides, Listeria monocytogenes*  and *Streptococcus pneumoniae* have all been implicated as etiologic pathogens. The ranking profile of the major causative organisms, however, depends majorly on the region of practice.

The major burden of Neonatal-Perinatal bacterial meningitis occurs in the developing world, however, most evidence derives from wealthy countries even though the spectrum of disease, etiology and prognosis may differ.

In this Chapter, we would dilate on the available evidence of Neonatal-Perinatal bacterial meningitis in developing countries; provide its detailed pathophysiologic process/pattern; describe the relevant clinical features at presentation; discuss its diagnosis and management strategy with particular highlights of adjuncts of steroids; indicate relevant differences from well-resourced settings; provide relevant lacunae in knowledge and comment on feasible preventive methods.

#### **2. Incidence of disease**

Bacterial meningitis is undoubtedly more common in the neonatal-perinatal period than at any other time in life. This newborn's gloomy feature of increased susceptibility to infection is due to its innate immature immune system that is deficient in humoral and cellular immune responses in phagocytic and in complement functions. In the developed\affluent world, mortality has dropped from nearly 50% in the 1970s to <10% currently, but morbidity, however, remains substantial, with 20–58% of survivors developing serious neurological sequelae, such as deafness.

Most worrisome is the fact that its incidence, mortality and morbidity in the developing world have remained unacceptably high; variably reported as between 40–58%. With a documented incidence of 6.5\1000 live births, the disease has shown a rising trend in Nigeria as against other more affluent regions maintaining relatively stable rates of less than 1\1000.

### **3. Etiopathogenesis**

The chance of occurrence of bacterial meningitis becomes highly likely in the newly born baby with presence of adverse risk factors. These risk factors can generally be grouped into Prenatal, Intrapartum, Natal or Postnatal categories; or into Maternal, Obstetrics, or Postpartum divisions. These include low birth weight [LBW], very low birth weight [VLBW] and preterm gestation; maternal risk factors of premature ruptures of membranes, prolonged rupture of membranes (> 24 hours), maternal colonisation with Group B Streptococcus (GBS), maternal chorioamnionitis, maternal peripartum pyrexia and low socioeconomic status. These factors are universally important and well recognized. **Table 1** illustrates some of these factors.

Table 1. Some well known predisposal risk factors to the occurrence of Neonatal-Perinatal meningitis.

#### **4. The main pathogens of disease**

22 Meningitis

world, mortality has dropped from nearly 50% in the 1970s to <10% currently, but morbidity, however, remains substantial, with 20–58% of survivors developing serious

Most worrisome is the fact that its incidence, mortality and morbidity in the developing world have remained unacceptably high; variably reported as between 40–58%. With a documented incidence of 6.5\1000 live births, the disease has shown a rising trend in Nigeria as against other more affluent regions maintaining relatively stable rates of less than

The chance of occurrence of bacterial meningitis becomes highly likely in the newly born baby with presence of adverse risk factors. These risk factors can generally be grouped into Prenatal, Intrapartum, Natal or Postnatal categories; or into Maternal, Obstetrics, or Postpartum divisions. These include low birth weight [LBW], very low birth weight [VLBW] and preterm gestation; maternal risk factors of premature ruptures of membranes, prolonged rupture of membranes (> 24 hours), maternal colonisation with Group B Streptococcus (GBS), maternal chorioamnionitis, maternal peripartum pyrexia and low socioeconomic status. These factors are universally important and well recognized. **Table 1**

Table 1. Some well known predisposal risk factors to the occurrence of Neonatal-Perinatal

neurological sequelae, such as deafness.

1\1000.

meningitis.

**3. Etiopathogenesis**

illustrates some of these factors.

The commonly involved pathogens of Neonatal-Perinatal bacterial meningitis often differ from community to community, region to region and continent to continent. The pathogens also frequently correlate with the degree of development, advancement and environmental hygiene, and thus what we encounter in the developing world differs from that of the developed\affluent world. In developed countries, the predominant pathogens identified from cerebrospinal fluid [CSF] are GBS, *Escherichia coli, Listeria monocytogenes*, other

\**Abbreviations:* Refs – References, Yr – Year, Pts – Patients, WHO – World Health Organization, N.A. – Not Available, FT – Full Term, RCT – Randomized Control Trial, +ve – Positive, WCC – White cell count, CSFs – Cerebrospinal fluids.

Table 2. Etiology of neonatal bacterial meningitis in developing countries

Gram-negative enteric bacteria and *Streptococcus pneumoniae*. Infections in the neonatal period are frequently divided into 'early onset', (first 5–7 days, implying vertical transmission) when frequently isolated bacteria include GBS, *E. coli* and *Listeria*

\**Abbreviations:* Refs – References, Yr – Year, Pts – Patients, WHO – World Health Organization, N.A. – Not Available, FT – Full Term, RCT – Randomized Control Trial, +ve – Positive, WCC – White cell

Gram-negative enteric bacteria and *Streptococcus pneumoniae*. Infections in the neonatal period are frequently divided into 'early onset', (first 5–7 days, implying vertical transmission) when frequently isolated bacteria include GBS, *E. coli* and *Listeria*

Table 2. Etiology of neonatal bacterial meningitis in developing countries

count, CSFs – Cerebrospinal fluids.

*monocytogenes,* and 'late onset', (after the first week of life, implying nosocomial or community acquired infection), when common organisms include Gram negative organisms, *staphylococci* and GBS.

However, in the developing world, the pathogen profile appears different with most studies isolating *Staphylococcus aureus* and other gram negative organisms as leading culprits. Although the rate of isolates of *Escherichia coli* and *Klebsiella aeruginosa* are similar between the developed and developing regions of the world, however, there remains a very significant less encounter with GBS in the latter.

The speculated reasons for this difference are multi-factorial, and could include cultural difference in modes of genital care, population differences in colonisation, genetic differences in immune response and possibly geographic differences in laboratory techniques for pathogen isolation and reporting. **Table 2** highlights the pathogen profile and pattern of Neonatal-Perinatal meningitis in developing countries.

A good evaluation was a WHO-supported multi-centre study [covering Ethiopia, The Gambia, Papua New Guinea and the Philippines], but it only attempted to determine etiological agents responsible for serious infections in young infants [≤90 days]. However, this study was limited by identifying only 40 cases of neonatal meningitis, and the findings varied immensely between centres, which narrowed the conclusions that could be drawn. It is pertinent that unusual pathogens were identified in some other studies, e.g. *Neiseria Meningitidis, Haemophilus Influenzae* type *b,* and *Salmonella typhimurium*. **Table 2** is particularly worthwhile as it demonstrates the geographic differences of causal pathogens of Neonatal-Perinatal meningitis, which could serve as good guide to empirical antibiotic therapy.

#### **5. Pathophysiology**

**Method of acquisition:** Meningitis is basically an infection of the meninges (membranes that surround the brain and spinal cord) that enters through the bloodstream from other parts of the body. Meningococcal disease was first described as early as 1805, when an outbreak spread through Geneva, Switzerland. However, it was not until 1887 that a causative agent of meningococcal meningitis was identified. The pathogens that cause bacterial meningitis are very common and live naturally in the back of the nose and throat.At any given time, 10% of the populations are carriers of the disease but never actually become sick. In fact, most cases of meningitis are acquired through exposure to asymptomatic carriers.

Meningitis can be spread via nose and throat secretions [e.g. coughing, sneezing]. However, meningitis is not considered to be a highly contagious disease. Casual contact or breathing in the air where a person with meningitis has been normally would not expose someone to meningitis because the causative organisms cannot live outside the body for much long to allow their survival.

Acute bacterial meningitis usually develops from an invasion of bacterial pathogens from mucosal surfaces in nasopharynx, sinus cavities, and middle ear space into the blood stream. It can also result from head injuries, penetrating wounds, or neurologic surgeries.

In neonatal-perinatal infants, mother-to-infant transmission and aspiration of intestinal and genital tract secretions during labour and delivery are common modes of transmission.

However, the most implicated mode of acquisition of infection is via the haematogenous route in preponderant cases worldwide.

Pneumococcal meningitis usually arises in the setting of sustained bacteraemia that permits bacterial penetration across the blood-brain barrier and into the subarachnoid space. Once present in the central nervous system, bacterial multiplication incites host cell toxicity and release of a broad range of cytokines [e.g., Interleukin-1, Interleukin-6, and Tumour Necrosis Factor-α] that increase inflammation and vascular permeability. This is the same pattern with the other meningitis-causing pathogens. The resulting injury to the cerebral microvasculature causes brain edema that in turn leads to intracranial hypertension. Unless treated, this process usually leads to mortality and\or increased morbidity, such as neural deafness.

The importance of *S. pneumoniae* as a cause of childhood meningitis has been well described. *S pneumoniae* is also by far the most common pathogen recovered from communityacquired recurrent meningitis, accounting for a majority of cases of recurrent meningitis, even in the newborn infant. The overall case-fatality rate is close to 30%.

*H. influenzae* type *b* meningitis, once the most prevalent form of meningitis in children, is now rarer in the developed world because of successful immunization practices [*H. influenzae* type *b* conjugates vaccine) in the past 2 decades. In fact, incorporation of this vaccine into the routine immunization schedule resulted in a 94% decline in the number of cases of meningitis caused by *H. influenzae* type *b* in developed countries.

#### **5.1 Detection of cases**

The meninges have no host defenses to fight off invading organisms. One of the most important things to determine when meningitis is suspected is whether it is bacterial or viral. If a bacterial pathogen is the culprit, it is essential to identify the specific causative agent so that the appropriate antibiotics can be prescribed immediately. If left untreated, bacterial meningitis can lead to severe complications such as brain damage, hearing loss, epilepsy and death. Viral meningitis on the other hand, is generally less severe and typically resolves on its own.

The specific diagnosis of Neonatal-Perinatal bacterial meningitis remains protean and problematic. Its identification generally depends on a high index of suspicion. Clinically, the disease is often subtle and indistinguishable from that a metabolic problem or any illness solely due to sepsis, and without meningitis. The symptoms commonly include, lethargy, fever – which is better described as temperature instability, excessive crying with difficulty at being consoled, irritability, poor feeding, apprehension, and subtle and\or frank neonatal seizures. Neck stiffness or nuchal rigidity is often not detectable because of relative immaturity of the cranio-spinal nerve bundles with deficient myelination, but may rarely be present. Other problems are bulging anterior fontanelle, opistothonic posturing and any other non-specific neurological features.

Positive culture of CSF remains the gold standard for diagnosis and should be performed on all neonates where sepsis is suspected unless a contraindication exists. However, in view of the anatomic immaturity of the blood-brain-barrier area, caution should be employed when interpreting CSF parameters in the premature neonate.

Gram stains of CSF may could also provide useful information, even if CSF culture is not available. Simultaneous blood cultures are often positive in 40–80% of cases. Furthermore, it is notable that Neonatal-Perinatal meningitis can be present even in the absence of CSF pleocytosis, and CSF protein and glucose levels are age related. The simultaneously assessed CSF:Blood glucose relationship should not be less than 50% in any neonate, and solely detected hypoglycorracia [CSF sugar of 0-<1.3mmol\L] is always diagnostic.

#### **5.2 Diagnostic methods**

26 Meningitis

However, the most implicated mode of acquisition of infection is via the haematogenous

Pneumococcal meningitis usually arises in the setting of sustained bacteraemia that permits bacterial penetration across the blood-brain barrier and into the subarachnoid space. Once present in the central nervous system, bacterial multiplication incites host cell toxicity and release of a broad range of cytokines [e.g., Interleukin-1, Interleukin-6, and Tumour Necrosis Factor-α] that increase inflammation and vascular permeability. This is the same pattern with the other meningitis-causing pathogens. The resulting injury to the cerebral microvasculature causes brain edema that in turn leads to intracranial hypertension. Unless treated, this process usually leads to mortality and\or increased morbidity, such as neural

The importance of *S. pneumoniae* as a cause of childhood meningitis has been well described. *S pneumoniae* is also by far the most common pathogen recovered from communityacquired recurrent meningitis, accounting for a majority of cases of recurrent meningitis,

*H. influenzae* type *b* meningitis, once the most prevalent form of meningitis in children, is now rarer in the developed world because of successful immunization practices [*H. influenzae* type *b* conjugates vaccine) in the past 2 decades. In fact, incorporation of this vaccine into the routine immunization schedule resulted in a 94% decline in the number of

The meninges have no host defenses to fight off invading organisms. One of the most important things to determine when meningitis is suspected is whether it is bacterial or viral. If a bacterial pathogen is the culprit, it is essential to identify the specific causative agent so that the appropriate antibiotics can be prescribed immediately. If left untreated, bacterial meningitis can lead to severe complications such as brain damage, hearing loss, epilepsy and death. Viral meningitis on the other hand, is generally less severe and typically

The specific diagnosis of Neonatal-Perinatal bacterial meningitis remains protean and problematic. Its identification generally depends on a high index of suspicion. Clinically, the disease is often subtle and indistinguishable from that a metabolic problem or any illness solely due to sepsis, and without meningitis. The symptoms commonly include, lethargy, fever – which is better described as temperature instability, excessive crying with difficulty at being consoled, irritability, poor feeding, apprehension, and subtle and\or frank neonatal seizures. Neck stiffness or nuchal rigidity is often not detectable because of relative immaturity of the cranio-spinal nerve bundles with deficient myelination, but may rarely be present. Other problems are bulging anterior fontanelle, opistothonic posturing and any

Positive culture of CSF remains the gold standard for diagnosis and should be performed on all neonates where sepsis is suspected unless a contraindication exists. However, in view of the anatomic immaturity of the blood-brain-barrier area, caution should be employed when

even in the newborn infant. The overall case-fatality rate is close to 30%.

cases of meningitis caused by *H. influenzae* type *b* in developed countries.

route in preponderant cases worldwide.

deafness.

**5.1 Detection of cases**

resolves on its own.

other non-specific neurological features.

interpreting CSF parameters in the premature neonate.

Early diagnosis of Neonatal-Perinatal bacterial meningitis is very crucial. Because the symptoms of meningitis can closely mimic other viral illnesses, many clinicians miss the diagnosis and prescribe inappropriate treatments. In many cases, a missed diagnosis can have fatal consequences. All healthcare givers should be aware that early recognition of the symptoms can be a matter of life and death, and they should become familiar with all possible signs and symptoms. A careful and thorough diagnostic work-up must be undertaken.

A detailed work-up line is shown in **Table 3.** The specific microbiological culture procedure of all major fluid areas of the body, i.e. blood, CSF and urine should be performed. This is often referred to as a 'Panculture Procedure', and has the value of identifying those neonates or perinates that could have a concomitant septicaemia and nephritis [UTI]. This is vital and highly needed since it has been well documented in several reports, that as highly as 30% of newborn infants with septicaemia also have concomitant meningitis.

The CSF must be examined for general appearance, consistency, and tendency to clot. CSF analysis should include cell counts (including a WBC differential), glucose and protein analysis, and Gram staining of the centrifuged sediment. The use of C-reactive protein [CRP] levels has been shown to play an important role in differentiating among the various types of meningitis. More recently, some workers recommended the use of serum procalcitonin level for better diagnostic and prognostic value than CRP or leukocyte count to distinguish between bacterial and viral meningitis. Their cases were, however, older children of 4months and above. It requires validation in the neonate and perinate.

Polymerase chain reaction has remained sensitivity and quick in detecting and differentiating between viral and bacterial meningitis.

The hands, ears, nose, throat and sinuses should be checked for the possible source of infection, and a latex agglutination test to detect bacterial antigens of *Staphylococcus aureus, Streptococcus pneumoniae, Neisseria meningitides, Haemophilus influenzae* type *b*, Group B Streptococcus, *Klebsiella* sps and *Escherichia coli* strains, can aid in the diagnosis of Neonatal-Perinatal bacterial meningitis. However, this test may lack sensitivity unless ultrasonic enhancement is used.

Newborn infants with suspected bacterial meningitis should also undergo testing for glucose, serum electrolytes and blood urea nitrogen, which could indicate the degree of dehydration and identify hyponatraemia and hypoglycaemia; common symptoms of meningitis.

Clinical clues signaling the presence of bacterial meningitis may include sinusitis, otitis, mastoiditis, infective endocarditis and characteristic skin infections [such as those seen in infections caused by herpes, simplex virus, varicella-zoster virus]. Cardiovascular instability

or focal neurologic signs such as papillary changes, hemi-paresis, and ocular palsies are indicative of bacterial meningitis. Patechial and purpuric rashes usually indicate meningococcemia or *H. influenzae* meningitis. Presence of arthritis may suggest the presence of *H. influenza* and *N. meningitides*, and head trauma or a chronically draining ear usually signals pneumococcal meningitis.

Table 3. Tests commonly utilized in the diagnosis of Neonatal-Perinatal bacterial meningitis

Bacterial meningitis in the newborn can be difficult to distinguish from other infectious diseases. To aid in the differential diagnosis, physicians should take a complete epidemiologic history, including contact with sick persons; maternal dietary habits, and\or illicit drug use; medication history; exposure to insects, rodents, or arthropods; and recent travel history.

Major epidemic of meningitis frequently occur during the hot dry seasons. Sub-Saharan Africa is plagued by the highest meningitis [*N. meningitides*] disease burden, is usually referred to as the "meningitis belt".

#### **5.3 Treatment intervention**

28 Meningitis

or focal neurologic signs such as papillary changes, hemi-paresis, and ocular palsies are indicative of bacterial meningitis. Patechial and purpuric rashes usually indicate meningococcemia or *H. influenzae* meningitis. Presence of arthritis may suggest the presence of *H. influenza* and *N. meningitides*, and head trauma or a chronically draining ear usually

Table 3. Tests commonly utilized in the diagnosis of Neonatal-Perinatal bacterial meningitis Bacterial meningitis in the newborn can be difficult to distinguish from other infectious diseases. To aid in the differential diagnosis, physicians should take a complete epidemiologic history, including contact with sick persons; maternal dietary habits, and\or

signals pneumococcal meningitis.

It cannot be overemphasized that treatment must be started early in the course of the disease, especially as it is of bacterial aetiology. Prompt intervention can reduce the risk of death to below 15%. If not treated as a medical emergency, bacterial meningitis can lead to seizures, coma, increased intracranial pressure, nerve damage, stroke and even death.

By identifying the causative agent, the appropriate antibiotic can be administered. The baby's age, co-morbidities and the status of his or her immune system can aid in this identification. For example, immunocompromised patients are at particular risk for infection with *S. pneumoniae*, *N. meningitidis*, *Listeria monocytogenes*, and aerobic Gram-negative bacilli. In the developing countries, *S. aureus* remains a highly predominant organism in the neonatal age, whereas GBS is rarely encountered. Antibiotic intervention only improves the baby's prognosis if the antimicrobial therapy is administered before the patient's clinical condition has deteriorated. If antibiotics are started when the baby is already in an advanced stage of the disease, the chances of survival is poor.

Administration of antibiotics can also protect the development of the disease among children, or parents who have been exposed to another case of meningitis. According to some investigators, giving the appropriate antibiotics to household contacts of the patient with meningococcal disease can reduce their risk of infection by 89%. Antibiotic therapy must be effective against common causative pathogens and must achieve adequate bactericidal activity without toxicity in the CSF. Most often used antibiotics include; ampicillin or penicillin and an aminoglycoside [e.g. Gentamicin] or a third-generation cephalosporin, such as ceftriaxone or cefotaxime. The recommendation of ceftriaxone includes the awareness that it may cause billiary sludge leading to jaundice in the neonate. Such caution appears to be theoretical, as in practice, the problem rarely occurs. Penicillin and gentamicin are widely available, cheap and the first line antimicrobial therapy in many resource-poor settings. In developed countries, initial therapy often includes some combination of three agents: Penicillin, an aminoglycoside and a third-generation cephalosporin – considered by some school-of-thought to be over use and miss use of antibiotics.

First-line therapy is usually either ampicillin and gentamicin or ampicilin and cefotaxime, or ceftriaxone and gentamicin. The value of the cephalosporins is their widely spaced dosage regimen with satisfactory better compliance. The use of cephalosporins has coincided with a reduction in mortality from neonatal meningitis in developed countries but with no associated fall in morbidity.

Gentamicin remains an effective antimicrobial, despite its small therapeutic window. Despite the fears of its causing renal toxicity and deafness, there is no documented occurrence of these complications during clinical use.

Third-generation cephalosporins (cefotaxime and ceftriaxone) are active against the major pathogens of neonates worldwide, including aminoglycoside-resistant strains. They have good CSF penetration and achieve adequate therapeutic concentrations in the CSF. Thirdgeneration cephalosporings were recommended in the multi-centre WHO study group of serious infections in young infants.

If available, vis-à-vis a resource-poor setting, cefotaxime and ceftriaxone are currently recommended for use in Neonatal-Perinatal bacterial meningitis in view of the added advantage of a longer half-life, allowing less frequent administration.

However, it is pertinent that empiric antibiotic choice should be tailored to local epidemiology, early versus late infections and whether the infection was nosocomially acquired.

#### **5.4 Adjunctive therapy**

The use of corticosteroids as an adjunct to antibiotic therapy has been shown to render treatment of bacterial meningitis more effective, especially in children by reducing CSF inflammation and hearing loss. This has been shown conclusively for disease caused by *H. influenzae* type b and *S. pneumoniae* and it is, therefore, now routinely used worldwide. Its efficacy is said to improve if administered before, or along with the antibiotics. Though few studies have documented the valuable effects of steroids [dexamathasone] as an adjunct in neonatal meningitis, more evaluation requires to be done without timidity or over anxiety by clinicians. **Table 4** elucidates the improved outcome with its use in Nigeria.

\* The disabilities and handicaps were: hearing-defects, subdural effusion, hydrocephalus, hemiparesis and recurrent afebrile seizures.

Table 4. Value of steroids (dexamethasone) and quality of recovery from Neonatal-Perinatal bacterial meningitis.

There was significant less mortality and improved full recovery with adjunctive use of steroids, p=0.006.

#### **5.5 The interplay of bacterial resistance**

Penicillin resistance is mediated by alterations in penicillin binding proteins (PBPs). PBPs are membrane-bound enzymes that catalyze the terminal steps in the assembly of the bacterial cell wall. The key PBPs involved in penicillin susceptibility includes PBP 1a, 1b, 2a, 2b, and 3. Strains with reduced susceptibility to penicillin also exhibit reduced susceptibility

Third-generation cephalosporins (cefotaxime and ceftriaxone) are active against the major pathogens of neonates worldwide, including aminoglycoside-resistant strains. They have good CSF penetration and achieve adequate therapeutic concentrations in the CSF. Thirdgeneration cephalosporings were recommended in the multi-centre WHO study group of

If available, vis-à-vis a resource-poor setting, cefotaxime and ceftriaxone are currently recommended for use in Neonatal-Perinatal bacterial meningitis in view of the added

However, it is pertinent that empiric antibiotic choice should be tailored to local epidemiology, early versus late infections and whether the infection was nosocomially

The use of corticosteroids as an adjunct to antibiotic therapy has been shown to render treatment of bacterial meningitis more effective, especially in children by reducing CSF inflammation and hearing loss. This has been shown conclusively for disease caused by *H. influenzae* type b and *S. pneumoniae* and it is, therefore, now routinely used worldwide. Its efficacy is said to improve if administered before, or along with the antibiotics. Though few studies have documented the valuable effects of steroids [dexamathasone] as an adjunct in neonatal meningitis, more evaluation requires to be done without timidity or over anxiety

\* The disabilities and handicaps were: hearing-defects, subdural effusion, hydrocephalus, hemiparesis

Table 4. Value of steroids (dexamethasone) and quality of recovery from Neonatal-Perinatal

There was significant less mortality and improved full recovery with adjunctive use of

Penicillin resistance is mediated by alterations in penicillin binding proteins (PBPs). PBPs are membrane-bound enzymes that catalyze the terminal steps in the assembly of the bacterial cell wall. The key PBPs involved in penicillin susceptibility includes PBP 1a, 1b, 2a, 2b, and 3. Strains with reduced susceptibility to penicillin also exhibit reduced susceptibility

by clinicians. **Table 4** elucidates the improved outcome with its use in Nigeria.

advantage of a longer half-life, allowing less frequent administration.

serious infections in young infants.

acquired.

**5.4 Adjunctive therapy**

and recurrent afebrile seizures.

**5.5 The interplay of bacterial resistance**

bacterial meningitis.

steroids, p=0.006.

to beta-lactam drugs such as cephalosporins. *S. pneumoniae* resistance to other antibiotic classes is also now widespread, and includes resistance to macrolides, trimethoprimsulfamethoxazole, chloramphenicol, and quinolones. Multiple mechanisms mediate resistance and are briefly described in **Table 5**. Drug resistance to a single class of antibiotics may also be mediated by multiple mechanisms. Acquired resistance to a particular class of antibiotics increases the likelihood that the strain will be resistant to other classes of antibiotics. For example, 94% penicillin-susceptible strains of S. pneumoniae were recently found to be susceptible to azithromycin, but 17% of penicillin-resistant strains were azithromycin-susceptible.

Resistance to macrolides, and trimethoprim-sulfamethoxazole is also widespread. Macrolides resistance is mediated by either an efflux pump [low-level resistance] or a ribosomal methylase [high-level resistance].

Penicillin-resistant strains are often resistant to cephalosporins such as ceftriaxone and cefotaxime. Vancomycin is active against all strains of S*. pneumoniae* but vancomycintolerant strains have now been described. The individual members of the flouroquinolone class demonstrate differential activity against *S. pneumoniae*.

Table 5. Mechanisms of antibiotic resistance of *S. pneumoniae*

#### **6. Conclusion**

It is intriguing that Neonatal-Perinatal bacterial meningitis continues to be a major cause of morbidity and mortality in the developing world. It is vital that more efforts are required for its control rather the offer of appropriate diagnosis and treatment. It is majorly necessary that efforts must be directed to community health education, provision of regular information, and a versatile up-keep of hygiene and routine cleanliness. The importance of immune boosting through vaccinations and their acceptance is further worthy, as prevention is always better than cure. Important differences in aetiology have been noted but early and focused treatment of established disease, with the use of steroid adjunct, remains essential.

#### **7. References**

information, and a versatile up-keep of hygiene and routine cleanliness. The importance of immune boosting through vaccinations and their acceptance is further worthy, as prevention is always better than cure. Important differences in aetiology have been noted but early and focused treatment of established disease, with the use of steroid adjunct,

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### **Neurologic Complications of Bacterial Meningitis**

Emad uddin Siddiqui *Aga Khan University Hospital Pakistan*

#### **1. Introduction**

34 Meningitis

[35] Molyneux E, Walsh A, Phiri A, Molyneux M. Acute bacterial meningitis in children

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the Royal Liverpool Children's Hospital, Liverpool, UK and the Queen Elizabeth Central Hospital in Blantyre, Malawi: a world of difference. *Annals of Tropical*

> Bacterial meningitis is a serious and potentially life threatening CNS infection. It often results in disabling or deaths in 170,000 patients each year worldwide. Younger children are predominantly at risk of bacterial meningitis, mainly because of their immature immune systems and malnutrition while lack of immunization practices also makes them more susceptible to significantly high morbidity & mortality. (Anderson, V. et al., 2004). Even with the provision of highly effective antibiotic therapy, death and long-term disabilities are the common but still seroius consequences of acute bacterial meningitis in developing countries. Common neurological complications in adult are hearing loss, motor deficit, cognition defect and speech problem, whereas sensorineural deafness, followed by seizure disorder and motor deficit are more common in children. Sixteen percent of pediatric patients from developed countries have neurological complications, while this figure rose 26 percent from developing countries. (Braff, LJ. et al., 1993). Two third of all pediatric deaths due to meningitis occur in low income countries and as many as 50% survivors of childhood meningitis experience some neurological sequel. (Mace, SE 2008)

> Neurological complications of meningitis can occur at any time during the course of disease and even after the completion of therapy. Neurological complications may either be focal or generalized or it may be of sudden or gradual in onset. Patients either remain conscious or may present with altered consciousness or even coma. Usually the complications develop during the course of acute bacterial meningitis but some of them manifest or persist as the long-term sequel such as; hearing loss, epilepsy, hemiplegia, neuropsychological impairment, developmental and learning disabilities. Shock or disseminated intravascular coagulation, frequently is associated with meningococcal meningitis. Pneumococcal meningitis is associated with the highest case fatality rate*.* Apnea and respiratory failure may occur with any bacterial meningitis, especially in infants. Post meningitis complications may occur in almost half of all cases, 81% of them may present with neurological sequel. A part of this may present with systemic sequel, while a quarter of them have both neurological and systemic complications. (Pfister, HW. et al., 1993)

#### **2. Risk factors for neurological complications**

There are multiple risk factors either directly or indirectly related to any one or more of the neurological complications as listed in Table 1. Extremes of age is directly associated with the consequences and prognosis. Organism type, virulence and number of bacteria entered, portal of entry along with the susceptibility of host all count in the development of neurological complications. Duration and progression of illness before initiation of effective antibiotic therapy is also associated with neurological complication. On the other hand mode of presentation, and compliance to the appropriate treatment or any associated comorbid may also have detrimental effect on patient neurological outcome and morbidity. Patients on immunosuppressive drug, chronic liver disorders, alcoholics, diabetics and patients with congenital or acquired immune deficiency disease, malignancy and HIV, are at increased risk of meningitis and its sequel as compare to general population. Streptococcus pneumoniae is associated with most of the sequel as compared to the other organisms.

Table 1. Complications of meningitis and its types

Several studies have been conducted to identify the clinical factors that are associated with adverse outcomes in children with bacterial meningitis. Unconsciousness early in the disease, multiple or prolong seizures (>72 hours), use of inotrops, and leucopenia are important predictors of adverse neurological outcome. It has been observed that patients with neurological symptoms lasted for >24hrs, focal neurological signs, ataxia, or deteriorating conscious level despite the commencement of adequate and appropriate therapy and serum sodium concentration <130 mmol/L are associated with adverse outcomes. Other clinical presentations of meningitis that are associated with increased risk of neurologic complications are low CSF glucose concentration, and CSF bacterial count of ≥10 cfu/ml. (Feldman, WE. 1997). Patients on ventilatory support and PRISM score of ≥20 in first 24 hours of admission are few other common clinical predictors associated with increased incidence of neurological complications. (Madagame, ET. et al., 1995)

#### **3. Altered mental status**

36 Meningitis

There are multiple risk factors either directly or indirectly related to any one or more of the neurological complications as listed in Table 1. Extremes of age is directly associated with the consequences and prognosis. Organism type, virulence and number of bacteria entered, portal of entry along with the susceptibility of host all count in the development of neurological complications. Duration and progression of illness before initiation of effective antibiotic therapy is also associated with neurological complication. On the other hand mode of presentation, and compliance to the appropriate treatment or any associated comorbid may also have detrimental effect on patient neurological outcome and morbidity. Patients on immunosuppressive drug, chronic liver disorders, alcoholics, diabetics and patients with congenital or acquired immune deficiency disease, malignancy and HIV, are at increased risk of meningitis and its sequel as compare to general population. Streptococcus pneumoniae is associated with most of the sequel as compared to the other organisms.

Neurological Systemic (Non Neurological)

Several studies have been conducted to identify the clinical factors that are associated with adverse outcomes in children with bacterial meningitis. Unconsciousness early in the disease, multiple or prolong seizures (>72 hours), use of inotrops, and leucopenia are important predictors of adverse neurological outcome. It has been observed that patients with neurological symptoms lasted for >24hrs, focal neurological signs, ataxia, or deteriorating conscious level despite the commencement of adequate and appropriate therapy and serum sodium concentration <130 mmol/L are associated with adverse outcomes. Other clinical presentations of meningitis that are associated with increased risk of neurologic complications are low CSF glucose concentration, and CSF bacterial count of ≥10 cfu/ml. (Feldman, WE. 1997). Patients on ventilatory support and PRISM score of ≥20 in

Prolong fever

Hyponatremia

Death

Bilateral adrenal hemorrhage

Septic shock and DIC Vasomotor collapse Loss of airway reflexes Respiratory arrest Pericardial effusion Hypothalamic and other endocrine dysfunction

**2. Risk factors for neurological complications**

**Acute onset**

pressure

Blindness

Ataxia

**Late onset**

Altered mental status/ coma

Subdural effusion or empyema

Hemiparesis or quadriparesis

Cerebrovascular abnormalities Neuropsychological impairment Developmental disability Intellectual deficit

Late onset seizure (epilepsy) disorder

Table 1. Complications of meningitis and its types

Acute onset Seizures

Cranial nerve palsies Hydrocephalus Sensorineural deficit

Cerebral edema and raised intracranial