Haemophilus Meningitis Treatment & Management

The first attempts at treatment, which resulted in only modest reductions in the high mortality rate of Haemophilus influenzae type b (Hib) meningitis, involved the administration of antisera generated by intrathecal inoculation of horses. Not infrequently, this form of immunotherapy had untoward immune consequences, including serum sickness, conjunctival edema, and anaphylaxis. Alexander developed much more effective antisera in rabbits in 1939.

Although sulfonamides proved disappointing at first, combining this antibiotic with Alexander’s antisera in 1942 resulted in the first great therapeutic breakthrough, with a reduction of the mortality rate to 26%, although the combination induced untoward immune-mediated reactions in more than 40% of patients.

The year 1944 saw the introduction of streptomycin. The use of this antibiotic—systemic and intrathecal, often in combination with either Alexander’s antisera or sulfadiazine or both—reduced the mortality rate to 3.4% by 1947. Chloramphenicol replaced streptomycin in 1950 because its excellent penetration of the blood-brain barrier eliminated the need for intrathecal treatment. In combination with sulfadiazine, chloramphenicol remained the treatment of choice until this role was assumed by ampicillin.

The most critical aspect of initial treatment of meningitis is prompt initiation of antimicrobial therapy, because any delay in treatment is associated with increased morbidity and mortality. Anti-inflammatory therapy remains controversial, but dexamethasone may help prevent hearing loss. When necessary, increased intracranial pressure (ICP) can be treated with mannitol.

Go to Meningitis, Meningococcal Meningitis, Staphylococcal Meningitis, Tuberculous Meningitis, Viral Meningitis, and Aseptic Meningitis for complete information on these topics.

Currently, the agent of choice for the treatment of Hib meningitis in children who are older than 6 weeks and younger than 6 years is a third-generation cephalosporin (eg, cefotaxime or ceftriaxone), given intravenously (IV). These agents are at least as effective as the older regimen of combination therapy with ampicillin and chloramphenicol and are more effective in children who are infected with microbes that are resistant to ampicillin or chloramphenicol. They are well tolerated, with few adverse effects.

In addition, third-generation cephalosporins can be effectively administered in fewer total daily doses. Thus, although the total daily dose of cefotaxime has usually been divided into 3 doses given at 8-hour intervals, evidence supports administration twice or even once daily. Likewise, the long half-life of ceftriaxone affords the opportunity, in selected cases, for a once-daily antibiotic regimen, enabling patients who have responded well to initial treatment to be discharged home for outpatient IV therapy to complete the course of treatment for Hib meningitis.

Once started, these cephalosporins are generally administered for a total 10-day course, although emerging evidence suggests that 7 days may be adequate for uncomplicated Hib meningitis. The course may be prolonged to a total duration of 14-21 days in complicated cases or in those manifesting prolonged or recurrent fever.

Although older studies suggested that the second-generation cephalosporin cefuroxime might be reliably effective for Hib meningitis, subsequent studies have not confirmed that reliance, and it is no longer recommended. The rejection of this drug as standard therapy is based on evidence that it is slower than third-generation cephalosporins in sterilization of cerebrospinal fluid (CSF) and that treatment may prove ineffective, with more prolonged illness, greater chance for hearing loss and other complications, and risk of recurrence of infection with discontinuation.

Meropenem may be considered a good alternative to the third-generation cephalosporins for the treatment of HiB meningitis.

Ampicillin and gentamicin remain the agents of empiric choice for those younger than 6 weeks because of the importance of gram-negative organisms in that age group and the rarity of Hib meningitis in such very young infants.

With the considerable decline in Hib meningitis among vaccinated children younger than 6 years, the percentage of cases of Streptococcus pneumoniae in that age group has increased. Furthermore, because resistance of S pneumoniae to both penicillin and cephalosporins is increasing in some parts of the world, vancomycin should be included in empiric therapy of children presenting with meningitis.

Disadvantages of ampicillin and chloramphenicol

Previously, ampicillin and chloramphenicol were recommended for the treatment of Hib meningitis. However, resistance to both these antibiotics has emerged. Specifically, strains of Hib produce beta-lactamase and others are resistant through reduced affinity for penicillin-binding proteins. Hib resistance to ampicillin may be found in beta-lactamase negative strains that have shown increasing prevalence in the past few years in Japan and elsewhere.

Alarmingly, some of these strains are also demonstrating resistance to cefotaxime and ceftriaxone. In situations where such beta-lactamase negative/ceftriaxone-resistant Hib strains are encountered, high-dose ceftriaxone (150 mg/kg/d) may be the treatment of choice. ^[23]

Resistance to chloramphenicol is mediated through bacterial elaboration of chloramphenicol acetyltransferase, which is found in more than half of all Hib isolates from children in some countries.

The emergence of resistant strains of Hib has been especially troublesome in developing nations, where the availability and cost of newer antibiotics may prevent patients infected with these strains from being effectively treated. Between 1994 and 2002, a Kenyan hospital noted that resistance susceptibilities to various antibiotics for H influenzae isolates were amoxicillin (66%), chloramphenicol (66%), and TMP-sulfa (38%). Most of this resistance was found in the Hib strains. ^[24]

In addition to the growing problem of resistance, chloramphenicol has other disadvantages. Toxic effects (eg, bone marrow suppression, diminished myocardial contractility) render it less desirable for use in children. Myocardial toxicity is more likely to arise in individuals in shock, which may be the case in fulminant Hib sepsis/meningitis.

Serum chloramphenicol levels must be monitored because of the considerable individual variation in pharmacokinetics. In addition, chloramphenicol has several interactions with drugs that are commonly used in the setting of meningitis. Coadministration with phenytoin may increase chloramphenicol concentration, and chloramphenicol may affect serum levels of phenytoin. Coadministration with phenobarbital may decrease chloramphenicol concentration.

These kinds of interactions do not arise with third-generation cephalosporins, whose pharmacokinetic reliability eliminates the necessity for monitoring of antimicrobial levels.

Experimental and pathological evidence strongly suggests that host immune responses to the cell wall constituents of lysed bacteria or other epitopes play roles in the pathogenesis of bacterial meningitis. Further, experimental investigations have produced support for the concept that corticosteroids may significantly reduce the prevalence of neurologic sequelae in individuals with meningitis.

Most clinical studies, including a meta-analysis, show that early use of dexamethasone improves outcomes of treatment, chiefly in preventing hearing loss. Two recent studies have been controversial. One was retrospective and the children in the steroid arm were sicker and more likely to be ventilated. The other study, a prospective study from Malawi, had a high percentage of children with HIV infection and most children seemed to present with severe illness and with a long delay before therapy. These studies emphasize 2 important points: (1) early administration of steroids (prior to or with the first dose of antibiotics) is beneficial and (2) the use of steroids after the development of severe neurological damage may be of limited benefit.

The Infectious Diseases Society of America considers the use of dexamethasone in the treatment of HiB meningitis in infants and children to be an A-I recommendation. ^[25]  European guidelines recommend a total duration of 4 days for Hib meningitis in children whereas American guidelines recommend the use of dexamethasone for 2–4 days in children with Hib meningitis. ^{[26, 27]}

The recommended dose is 0.15 mg/kg every 6 hours for the first 2 days after initial diagnosis and treatment. Administering the dexamethasone either before or concomitant with the first dose of antimicrobial therapy is likely of considerable importance if a positive effect is expected.

No evidence indicates that this form of treatment with dexamethasone, administered during the first 2 days of illness, compromises the outcome of appropriate antimicrobial therapy. This may be especially true if such treatment is continued for only 2 days, although data to confirm this point of view are not currently available.

If dexamethasone treatment is elected, care must be exerted to avoid complications such as gastrointestinal hemorrhage.

Patients with Hib meningitis require careful attention to metabolic parameters, close attention to timely replacement and management of IV lines to prevent secondary infections, and management of pulmonary and cardiovascular function as necessary in light of the severity of illness.

Head circumference, fontanelle pressure, funduscopy, and other measures of secondary increases in intracranial volume due to postmeningitic hydrocephalus or the development of extra-axial collections (eg, abscess, empyema, subdural hemorrhage, noninfectious subdural collections) should be monitored as indicated in individual cases. Repeat scans of the intracranial contents should be ordered as needed when unexpected deteriorations of function occur that might be explained by structural processes.

Surgical intervention may occasionally be required in infants or children who develop increased ICP. Intervention in such instances may be limited to the placement of a device to monitor ICP in order to facilitate treatment. In other instances, surgery may be required to alleviate noncommunicating hydrocephalus.

The first vaccines against Hib were produced from the polysaccharide capsule material and were licensed in 1985 for routine use in children older than 2 years. However, these vaccines proved ineffective for children younger than 18 months (who are those most likely to develop Hib meningitis) and had only moderate effectiveness in older children. ^[28]

Subsequently, new vaccines were developed that conjugated a carrier protein to the polyribosyl-ribitol-phosphate (PRP) molecule. These were first licensed in the United States in 1987 but were not approved for use in children as young as 2 months until 1990. All of these agents have demonstrated a considerable degree of immunogenicity, even in very young children. For more information, see Medication.

The failure rate of Hib conjugate vaccines is exceedingly low. Such failures are related, in slightly less than half of all cases, to defined underlying immunological deficiency or other pertinent risk factors. Immunoglobulin (Ig) deficiency and asplenia are the most commonly encountered impediments to effective vaccination. ^[29]

IgG3-deficient individuals, who may be infection-prone due to low capacity to generate protective antibody levels have been shown to respond well to immunization with the conjugate ACT-HIB vaccine, achieving sufficient levels of antibodies to provide protection against both Hib infections and tetanus. ^[30]

Side effects of these vaccines are difficult to assess because Hib vaccination is administered concurrently with other vaccinations. The most commonly reported reactions are local erythema, local induration, and irritability. Fever has also been reported. No serious adverse reactions have as yet been clearly linked to the currently used Hib vaccines.

Epidemiologic effects of Hib vaccination

Several studies have demonstrated a significant reduction in the rate of carriage after vaccination. Carriage of the organism increases the risk of infection in the colonized individual. Reduction in rates of carriage also reduces the exposure to other children who may be at risk. The achievement of reduced nasopharyngeal carriage in older children, who received conjugated vaccines before their approval for use in infants, may account for the fact that many studies showed a decline in incidence of Hib meningitis in infants who were not as yet eligible for vaccination.

Several studies in the United States and abroad have demonstrated a significant reduction in the incidence of invasive Hib infection soon after the introduction of the vaccine. Within the United States, the incidence of invasive Hib diseases has fallen from 85% to 90%. These results have been reproducible in both regional and multistate studies and are not accounted for by interannual variations. The population that received the greatest benefit is that consisting of infants younger than 14 months, a group with the highest incidence of Hib meningitis.

North American immunization recommendations now include as many as 24 vaccines to be administered in an injectable form by 18 months of age. Because of pain as well as compliance, combination vaccines have been recommended where such combinations have been found to be effective.

Among these vaccines, a particularly important combination is that which immunizes against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV/Hib). When instituted in a proper and complete schedule, this combination vaccine has been shown to be safe and effective for primary infant immunization and toddler booster immunization. ^[31]

Canada, which has had an immunization program since 1992, has discerned a shift in population prevalence for Hib meningitis, with cases occurring more frequently in infants younger than 6 months. Two thirds of cases occur in individuals with no or incomplete vaccination (due to age, parental refusal, or other delaying circumstances). However, some cases occur in individuals who have completed the primary series of immunizations.

It has also been demonstrated in Canada that the conjugate vaccine efficacy is not affected by coadministration of other typical age-indicated vaccinations. Higher case-fatality rates are observed in the postimmunization epoch in Canada and in older individuals, and two thirds of these cases occur in males. ^[32]

Studies in the Netherlands have detected a disturbing trend toward an increase in the rate of invasive Hib disease in children younger than 5 years. The increased annual incidence is from 0.66 cases per 100,000 in 1998 to 2.96 cases per 100,000 in 2001. The investigators are concerned that this increase is due to the change from the use of whole-cell pertussis vaccine to the conjugate DTaP-Hib vaccine. This newer vaccine has been associated with the achievement of lower levels of anti-Hib antibodies, although in the Netherlands that effect has not been observed. ^[33]

Unfortunately, even vaccination producing “adequate” Hib antibody levels may in rare instances not prevent the development of severe Hib infection, as has been observed recently in a case of fatal Hib septic purpura fulminans. ^[29]

Despite effective reduction in the incidence of disease, the case-fatality rate has remained about the same in the United States in the era of effective vaccination as it was prior to the availability of an effective vaccine. However, fewer deaths related to Hib meningitis in vaccinated populations have occurred annually since the number of cases has been so greatly reduced.

On the other hand, in developing nations, the effect of vaccination on case-fatality and case-morbidity rates may be expected to be much higher, since these outcome measures are so much worse in nations where diagnosis and treatment may be delayed due to the inadequacies of transportation and medical infrastructure.

Moreover, in developing nations the rates of antibiotic resistance (which increase morbidity and mortality) is high and steadily increasing. In Pakistan, where 35% of childhood meningitis is Hib, occurring mostly in the first year of life, the rates of Hib resistance to antibiotics is approximately 33% for ampicillin, 22% for chloramphenicol, and 49% for cotrimoxazole. ^[20]

The increasing role of nontypeable strains of H influenzae, for which no effective immunization is available, has been noted. So has recognition of such typeable strains as H influenzae type f (Hif), suggesting that the place of Hib as the overwhelmingly most common cause of invasive disease due to H influenzae may be taken to some degree by other capsular types. It is troubling that there has been possible clonal expansion of several strains of Haemophilus that are the same in the United States and Denmark. ^[34]

Hib immunization programs in developing nations

Some of the current controversies and difficulties concerning establishment of immunization programs in developing nations have been discussed earlier. (See Epidemiology.)

In 2005, the Global Alliance for Vaccines and Immunization (GAVI) created the Hib Initiative, aiming to spend $37 million, over a 4-year period, for the funding of immunization programs in countries where immunization is inadequate. Institution of vaccination programs has been delayed not only by insufficient funding but also by considerations such as establishing current rates of infection and discerning which regions of the country contain children at greatest risk.

The importance of such immunization programs, irrespective of the controversies concerning regional annual incidence of Hib meningitis, is the fact that, in many targeted countries, Hib meningitis has much higher rates of morbidity and mortality than in wealthier nations with superior infrastructure, such as roads and hospitals. Thus, in rural Papua New Guinea, as many as 63% of children surviving meningitis (excluding a rather high rate of children lost to follow up) manifested major neurological sequelae.

The high rates of morbidity and mortality have been ascribed in part to the high rates of resistance to chloramphenicol and the unavailability of third-generation cephalosporins. However, the introduction of greater supplies of third-generation cephalosporins cannot be expected to significantly lower these rates, since nations such as Papua New Guinea, are unavoidably plagued by delayed presentation of sick children to centers capable of administering appropriate antibiotic treatment.

A major issue in Hib immunization is that the expense of vaccination, amounting to more than $2 US per person, is considerable for many nations. Accordingly, those who are on the front lines of this healthcare problem have pleaded for wealthier nations to assist in sponsoring vaccination and encouraging vaccine manufacturers to lower the costs of vaccines. ^[35]

Another issue is that the risk for severe outcomes from Hib infections may be increasing with the appearance of more examples of antibiotic-resistant strains. Treatment of these strains requires utilization of increasingly expensive antibiotics. In comparison with the growing cost of antimicrobial therapy, the relatively small expense of immunization may come to appear advantageous.

In order both to protect the children of developing countries and to limit the appearance of resistant strains, there seems every reason for the nations of the world to consider underwriting universal childhood immunization as a matter not just of international consideration but also of international self-interest. To date, however, this logical formulation has not resulted in adequate support from wealthier nations for such a program.

GAVI has approved 15 of 75 nations eligible for approval for vaccine introduction. Unfortunately, 26 countries that account in total for most of the world’s children have as yet provided too little data for consideration of approval for vaccine introduction.

Equally unfortunate is the fact that the officials of some countries that have received assistance for the introduction of Hib vaccines have expressed doubt as to whether the vaccine has proven beneficial and provided no practical plan for sustaining the administration of vaccines after introductory financial support was withdrawn, hence, the importance of gathering adequate information before and after the effective introduction of immunization.

No specifically pertinent dietary issues exist. Very ill patients who are unable to receive oral nutrition should, as early as is feasible, receive nutrition as IV hyperalimentation or via the placement of enteric feeding tubes.

The activities of infants and children during the acute phase of illness are dictated by the nature of their disease and necessity of providing various forms of therapy. In some instances, various forms of sedation or restraint are necessary to allow respiratory intervention or other forms of support. Activity should be limited by reduction of stimulation, and in some cases, sedation (eg, in cases where intracranial pressure is elevated). Elevation of the head of the bed is indicated in such cases.

Activities during the phase of recuperation are indicated by the nature and degree of recovery. No generic limitations of activity are associated with the acute or subsequent phases of Hib meningitis.

Consultations may be sought during the acute phase of illness from infectious disease specialists, neurosurgeons, or pediatric intensivists. Hearing testing should be performed at the conclusion of treatment, and posthospitalization interventions for such deficits as are found should be arranged.

Infants and children with prolonged courses or poor outcomes may require consultations from pediatric gastroenterologists. Physical and occupational therapy evaluations and therapy should be initiated as soon as is judged feasible in cases where neurologic abnormalities persist after initial treatment. Children who develop a chronic disability (eg, static encephalopathy), in time, may require the services of pediatric developmental specialists and pediatric orthopedic surgeons.

Patients may require care for the management of deficits resulting from Hib meningitis, including static encephalopathy, seizures, behavioral changes, or epilepsy. In some instances, patients may require anticonvulsants, analgesics, and medications to promote sleep or to attenuate behavioral, attention, or learning problems.

Management of persistent deficits

Some sequelae of Hib meningitis are transient; others lead to chronic or even permanent problems. Despite adequate treatment of children with Hib meningitis, approximately 20-40% are left with persistent sequelae. Some studies report that deficits are present in more than 50% of survivors. Permanent deficits are more likely in patients whose diagnosis and treatment is delayed and in those who are treated with less effective antibiotics (eg, ones to which the pathogens are resistant). The general categories are as follows:

• Seizures and epilepsy

• Hearing loss

• Other cranial nerve deficits

• Ataxia

• Hemiparesis

• Cognitive and behavioral disturbances

Seizures and epilepsy

Seizures that occur on presentation and during the earliest acute phase of Hib meningitis do so because of transient focal derangements in cortex or because of metabolic disturbances such as hyponatremia or hypoglycemia. Treatment may require the administration of anticonvulsants, the choice of which involves consideration of type of seizures, age of patient, and route of drug administration.

During the acute phase of presentation, care must be taken to diagnose and appropriately treat seizures prior to sedating or paralyzing patients for such procedures as brain imaging. Failure to do so may permit seizures to persist unrecognized for intervals of 40 minutes or more, which may have a very deleterious effect on outcome.

Occasionally, children with meningitis manifest subtle change in mental status in the wake of prolonged generalized seizures. Signs of such a process include poor responsiveness and the presence of widespread irregularly repetitive minipolymyoclonic jerks or twitches. Electroencephalographic assessment may be necessary.

Initial administration of anticonvulsants may precede discernment of the cause of seizure in cases in which seizures are prolonged or may increase ICP or metabolic demand. In such instances, children are generally treated with IV benzodiazepines, phenytoin, or phenobarbital. The decision to continue providing maintenance anticonvulsant treatment during the course of hospitalization depends on the cause and severity of seizures as well as the likelihood of recurrence.

Epilepsy, which may be difficult to control despite multiple antiepileptic medications, is present in less than 10% of survivors. The first seizure after the acute phase usually occurs within the first 2 years, although it may occur much later. Seizures are generally focal or have a focal onset. Most patients with epilepsy had transient focal seizures during the acute phase. However, seizures during the acute phase do not independently predict the occurrence of late seizures.

The presence of a persistent neurologic deficit other than sensorineural hearing loss is a risk factor for late manifestation of seizures (ie, seizures appearing for the first time in the late stages of hospitalization or after a period of weeks to years after discharge). In one study, all patients with a persistent deficit other than sensorineural hearing loss went on to have recurrent seizures after Hib meningitis.

Provision of appropriately selected anticonvulsants with consideration of seizure type and age of patient is necessary in patients with persistent seizures. Generally, patients respond well to treatment and have no recurrence for the ensuing year. In such cases, medications may be discontinued at the end of a year of treatment with small risk for recurrence. A second group continues to have seizures despite the first appropriately chosen drug. Their seizures remain difficult to control despite multiple anticonvulsants.

Occasionally, persistent seizures manifest in children who have had Hib meningitis but who recover fully and without any evidence on examination of focal neurologic deficits. These children are usually found to have structural brain abnormalities on brain imaging. In some of these cases, if seizures are intractable, as well as in cases where persistent deficits are mild or moderate, epilepsy surgery can be considered at an appropriately remote time from acute hospitalization.

Hearing loss

Hearing impairment is a common complication of meningitis. It is among the most common sequelae of Hib meningitis, occurring in about 20% of cases, although reports indicate a range of 10-30%. Hearing loss is sensorineural and may be unilateral or bilateral, with deficits ranging from mild hearing loss to deafness in the involved ear. Persistent hearing deficits may be associated with learning disabilities and language delay.

The actual mechanisms of damage to the hearing system are not fully understood. The absence of all waveforms on brainstem auditory evoked response (BAER) testing in these patients suggests a peripheral process. One explanation of injury is that, during the acute phase of illness, the eighth cranial nerve becomes encased by inflammatory exudate within its sleeve in the subarachnoid space.

Another possible mechanism is bacterial invasion of the spiral ganglia or cochlear perilymph via the internal auditory canal or cochlear aqueduct, resulting either in direct damage or in damage secondary to toxins or inflammatory products. Evidence for either of these mechanisms has been found in pathological studies.

Although sensorineural hearing loss is the most common finding, occasional patients with postmeningitic deafness are found to have conductive hearing loss. This type of deficit may result from the otitis media that fairly commonly precedes the development of Hib meningitis. Unlike sensorineural hearing loss, conductive hearing deficits resolve without permanent impairment.

Other cranial nerve deficits

Cranial neuropathies other then the eighth cranial nerve may occur. The involvement of cranial nerves other than the eighth is found in approximately 6% of children who have had Hib meningitis. Nerves most commonly involved are the facial, abducens, and oculomotor, but any of the nerves may be involved.

The mechanisms for these forms of injury include the inflammatory investment of the nerve within the nerve sheath near the brainstem (ie, due to the basilar meningitic inflammatory process), or they may be injured by compression due to elevation in intracranial pressure.

Ataxia

Ataxia is among the less common manifestations of Hib meningitis. It is typically sensory/vestibular in origin. Although it occurs less often than hearing deficits, the presumed mechanism of disease is similar to that of sensorineural hearing loss—namely, inflammatory investment of the vestibular division of the eighth cranial nerve. It is generally a self-limited process, although it is predictive of more permanent hearing loss.

Hemiparesis

Hemiparesis is found in approximately 6% of children recovering from Hib meningitis. In some instances, it is due to cerebral strokes that occur because of vasculitic inflammation of the brain. In other instances, it is the result of large subdural effusions that are commonly observed in meningitis.

Cognitive and behavioral disturbances

Cognitive and behavioral disturbances are found in as many as 40% of children who have had Hib meningitis. Many studies have been undertaken to evaluate cognitive impairment after meningitis. When compared with siblings closest in age, children who have had meningitis have lower average full-scale intelligence quotients (IQs). The magnitude of difference is greater than one standard deviation in 30% of cases. In one such study, 28% of patients were found to have significant handicaps, including 11% with mental retardation.

In addition, a wide range of neurologic and learning disabilities is found in a large percentage of survivors who are successfully treated with antibiotics and subsequently considered to be normal by parents, teachers, and peers.

However, more recent studies have not demonstrated large differences in intellectual outcomes. No difference was detected in the IQ between index cases and nearest-age siblings. Differences that were significant were mild and of questionable clinical significance.