Haemophilus Influenzae Infections

 

Haemophilus influenzae is a small (1 µm X 0.3 µm), pleomorphic, gram-negative coccobacillus. It is a nonmotile, non–spore-forming, fastidious, facultative anaerobe. Some strains of H influenzae possess a polysaccharide capsule. These strains are serotyped into 6 different types (a-f) based on their biochemically different capsules. Some strains have no capsule and are termed nonencapsulated H influenzae or nontypeable H influenzae (NTHi). The different strains can be identified with slide agglutination for serotyping or polymerase chain reaction (PCR) for capsular typing.

The most virulent strain is H influenzae type b (Hib), with its polyribosyl ribitol phosphate (PRP) capsule. It accounts for more than 95% of H influenzae invasive diseases in children and half of invasive diseases in adults, including bacteremia, meningitis, cellulitis, epiglottitis, septic arthritis, pneumonia, and empyema. Less-common invasive Hib infections include endophthalmitis, urinary tract infection, abscesses, cervical adenitis, glossitis, osteomyelitis, and endocarditis.

The other encapsulated strains H influenzae occasionally cause invasive disease similar to that of Hib. H influenzae type A (Hia) has been known to cause invasive disease (eg, meningitis) clinically indistinguishable from that caused by Hib. In a retrospective study in Canada conducted from 2000-2010, of the 130 H influenzae infections reported, 56% were Hia. Meningitis, bacteremia, and pneumonia were the most common clinical presentations.[7]

The nonencapsulated, or NTHi, strains cause mucosal infections, including otitis media, conjunctivitis, sinusitis, bronchitis, and pneumonia. Less commonly, these strains cause invasive disease in children but account for half of the invasive infections in adults. The population structure of NTHi demonstrates substantial genetic diversity, as opposed to the clonal nature of Hib.[8] Furthermore, the outer membrane proteins of NTHi show high strain-to-strain variability, making vaccine development a challenge.[7, 9]

The Hib carriage rate is 2-4% in children aged 2-5 years, the age when children usually become colonized. Hib carriage rates are lowest in adults and infants and highest in preschoolers. Since the advent of conjugate Hib vaccine, the nasopharyngeal carrier rate has decreased (< 1% in vaccinated individuals). Only a small percentage of H influenzae carriers develop invasive disease. The frequency of Hib infections in patients with asplenia, splenectomy, sickle cell disease, malignancies, and congenital or acquired immunodeficiencies is higher than in individuals without these conditions. Unvaccinated infants younger than 12 months with a history of invasive disease have a higher risk for recurrence than vaccinated infants.[10]

In contrast, NTHi carriage rates can be as high as 70% or more.[11]

Currently, the incidence of Hib invasive diseases has greatly decreased in the United States because of the wide spread of the Hib conjugate vaccine, whereas NTHi strains have become the most common cause of invasive disease in all age groups.

In countries outside the United States with established Hib immunization programs, such as England and Wales, NTHi is now the cause of nearly all invasive H influenzae diseases across all age groups.[7]

In Kamikawa subprefecture of Hokkaido, Japan, the incidence rate of H influenzae infection ranged from 15.1-36.3 per 100,000 population from 2006-2011. The Hib vaccine was introduced in November 2008, but vaccination rates rose to more than 90% only in December 2010, when Hib immunization became national policy. Thus, the rates dropped to 10.4 per 100,000 in 2012 and then to zero after 2013. No Hib meningitis cases have been reported since 2012, demonstrating the value of the vaccine in terms of case reduction.[12]

However, in many developing countries where Hib vaccination is not routine, invasive Hib disease is still a significant cause of morbidity and mortality.

During the pandemic, there was a reduction in H influenzae cases in both the northern and southern hemispheres along with S pneumoniae and N meningitidis. Specifically, the relative risk of H influenzae invasive disease decreased by 49% from meta-analytic data. Unfortunately, cases from H influenzae, S pneumoniae and N meningitidis were increasing again towards the end of 2021.[13]

The nomenclature (Haemophilus is Greek for "blood loving") acknowledges the fact that H influenzae requires 2 erythrocyte factors for growth: X (hemin) and V (nicotinamide-adenine-dinucleotide). These factors are released following lysis of red blood cells, thereby allowing growth of this fastidious organism on chocolate agar. H influenzae consists of 8 biotypes; biotype 3 (Haemophilus aegyptius) is associated with Brazilian purpuric fever, and biotype 4 is a neonatal, maternal, and genital pathogen. Humans are the only natural hosts. NTHi strains are a common resident of the nasopharyngeal mucosa and, in some instances, of the conjunctivae and genital tract.

Transmission is by direct contact or by inhalation of respiratory tract droplets. Nasopharyngeal colonization of encapsulated H influenzae is uncommon, occurring in 2-5% of children in the prevaccine era and even less after widespread vaccination. The incubation period is not known. A larger bacterial load or the presence of a concomitant viral infection can potentiate the infection. The colonizing bacteria invade the mucosa and enter the bloodstream. The presence of antibodies, complements, and phagocytes determines the clearance of the bacteremia. The antiphagocytic nature of the Hib capsule and the absence of the anticapsular antibody lead to increasing bacterial proliferation. When the bacterial concentration exceeds a critical level, it can disseminate to various sites, including meninges, subcutaneous tissue, joints, pleura, pericardia, and lungs.

Host defenses include the activation of the alternative and classical complement pathways and antibodies to the PRP capsule. The antibody to the Hib capsule plays the primary role in conferring immunity. Newborns have a low risk for infection, likely because of acquired maternal antibodies. When these transplacental antibodies to the PRP antigen wane, infants are at high risk of developing invasive H influenzae disease, and their immune responses are low even after the disease. Therefore, they are at high risk for repeat infections since prior episodes of H influenzae do not confer immunity. By age 5 years, most children have naturally acquired antibodies. The Hib conjugate vaccine induces protection by inducing antibodies against the PRP capsule. The Hib conjugate vaccine does not provide protection against NTHi strains. Since the widespread use of the Hib conjugate vaccine, NTHi has become a more common pathogen.

Although NTHi lacks a polysaccharide capsule, the expression of lipooligosaccharides (LOS) allow it to adhere and evade complement-mediated responses contributing to its virulence. Phase variable expression of genes enables it to adapt to the upper respiratory tract and the blood. The presence of phosphorylcholine (PCho) in the LOS decreases the release of IL-1β thereby dampening inflammation and facilitating colonization. In the blood, PCho expression is reduced as it increases CRP and IgM binding which facilitates complement-mediated killing. This allows survival of NTHi l in human serum.[14]  

The NTHi strains colonize the nasopharynx in up to 80% of individuals. The spread of bacteria by direct extension to the eustachian tubes causes otitis media. Spread to the sinuses leads to sinusitis. Spread down the respiratory tract results in bronchitis and pneumonia. Eustachian tube dysfunction, antecedent viral upper respiratory tract infection (URTI), foreign bodies, and mucosal irritants, including smoking, can promote infection. In patients with underlying chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF), NTHi frequently colonizes the lower respiratory tract and can exacerbate the disease.

NTHi strains form biofilm in vitro and ex vivo and have been implicated in chronic infection such as otitis media, sinusitis, and bronchitis. NTHi biofilm formation was found in patients with CF on the apical surface of airway epithelia with decreased antibiotic susceptibility. Studies into the nature of this biofilm structure and proteins will help develop strategies to fight chronic infections. Persons at risk for invasive H influenzae disease include those with asplenia, sickle cell disease, complement deficiencies, Hodgkin disease, congenital or acquired hypogammaglobulinemia, and T-cell immunodeficiency states (eg, HIV infection).

NTHi infection appears to disturb epithelial integrity and barrier function owing to the destruction of cell-cell contacts, which is believed to be a prominent feature in NTHi infection and has been related to a decrease in both E-cadherin mRNA and protein-levels in lung epithelial cells from patients with chronic bronchitis.[15]

Children younger than 4 years and contacts (eg, household and daycare) of individuals with Hib disease are at higher risk for infection. More research is needed to determine the risk factors for non–type B H influenzae and NTHi. However, persons with sickle cell disease, individuals with asplenia, individuals with HIV infection, persons with immunoglobulin deficiencies and complement component deficiencies, hematopoietic stem cell transplant recipients, patients undergoing chemotherapy or radiation therapy for malignant neoplasms, and American Indians and Alaska Natives are at higher risk for invasive H influenzae disease.[16]

United States

Before a vaccine became available in 1988, the annual attack rate of invasive Hib disease was estimated at 64-129 cases per 100,000 children younger than 5 years. By 2000, the number of cases in children younger than 5 years decreased by more than 99%. With the success of the Hib conjugate vaccine, at least half of invasive H influenzae infections are now caused by the nonencapsulated strains, and Hib meningitis has almost disappeared in the United States and Canada.

In 2006, the Active Bacterial Core Surveillance Report for H influenzae infection reported the following prevalences in 10 studied states (with a total study population of 35,599,550 persons):

• Hib infection - 0.04 cases per 100,000 general population
• Non-Hib infection - 0.36 cases per 100,000 general population
• NTHi infection - 0.99 cases per 100,000 general population (NTHi infections accounted for 353 of the 551 H influenzae infection cases reported in this series. ^[17] )

The latest Active Bacterial Core Surveillance Report for H influenzae infection in 2015 reported the following prevalence rates in 10 studied states (with a total study population of 43,912,887 persons):

• Hib infection: 0.02 cases per 100,000 general population
• Non-Hib infection: 0.42 cases per 100,000 general population
• NTHi infection: 1.24 case per 100,000 population (NTHi infections accounted for 544 of the 822 H influenzae infection cases reported in this series. ^[18] )

Meanwhile, the prevalence of Hia infections has increased in some countries since the advent of the Hib conjugate vaccine. However, in the United States, the number of Hia infections reported has remained constant.[19, 20]

International

Before vaccines became available, invasive Hib disease was a leading infectious illness among children worldwide. Hib vaccine is routine in the Americas, most of Europe, and a few countries in Africa and the Middle East.

In the 1990s, the frequency of Hib diseases decreased remarkably, and even developing countries reported only 2-3 cases per 100,000 of the population younger than 5 years.

In Canada, 10 centers reported 485 cases of invasive H influenzae disease in 1985. In 2000, 8 years after Canada implemented their Hib immunization program, their Immunization Monitoring Program, ACTive (IMPACT) reported only 4 cases. A report of invasive Hib disease in Canadian children identified 29 cases from 2001-2003. The number of cases progressively decreased over the 3 years, with 16 cases reported in 2001, 10 in 2002, and only 3 cases in 2003. A total of 15 cases of meningitis were reported. Six cases of pneumonia with bacteremia and 4 cases of epiglottitis were reported. Two Hib-related deaths occurred. Twenty of these children were unvaccinated or incompletely vaccinated, and 11 were younger than 6 months. Eight of the 9 children who had completed the vaccination series were immunocompromised or had other predisposing conditions. The report noted that the number of cases in older children was unchanged from previous years and that protection did not decline with age.

In England and Wales, the Hib vaccine was introduced in 1992, and the number of invasive Hib cases in children and adults dramatically decreased. Some felt that this was because of herd immunity due to interruption of transmission from immunized children to those who were unvaccinated. However, from 1998, the number of Hib cases was noted to be rising, and, in 2002, 134 cases occurred in children aged 4 years or younger. The increase in invasive Hib in England and Wales was also seen in persons aged 15 years and older and reached prevaccine levels. This was associated with reduced antibody concentration in the older age group. This reduction in herd immunity may be due to reduced transmission of Hib organisms from persons who were vaccinated to adults who were unimmunized, providing fewer opportunities for boosting of natural immunity.

In Africa and Asia, Hib vaccination coverage is still suboptimal,[21] so Hib remains an important disease pathogen. Although measures have been taken to immunize infants and children against Hib in developing countries, the progress has been relatively slow, partly because of financing for the vaccine, sustainable immunization programs, and the need for data on the burden of invasive Hib disease. In Lambok, Indonesia, from 1998-2002, high incidences of vaccine-preventable Hib meningitis and Hib pneumonia were reported in children younger than 2 years. In a district in Malawi, Africa, the incidence of H influenzae meningitis decreased from 20-40 per 100,000 to zero in 2005 after the vaccine was introduced in 2002.

However, a study of invasive disease due to H influenzae in South Africa from 2003-2009 found an increase in the incidence the disease in vaccinated children and concluded that a revision of the Hib conjugate vaccine recommendations should be considered.[22]

In many developing countries where Hib vaccine is not administered, Hib infection is a major cause of lower respiratory tract infections and is the leading cause of deaths due to bacterial pneumonia in children.[23]

A prospective multicenter (10 primary healthcare centers) study of pediatric nasopharyngeal carriers of H influenzae was conducted in the Mediterranean coastal region of Spain, and results showed that all were NTHi. Among all the isolates, 20% were resistant to ampicillin (10% of which were beta-lactamase–producing). During winter, carriage rates more than doubled.[24]

In 12 European countries from 2007-2014, NTHi infections comprised 78% of all H influenzae cases, increasing in those younger than 1 month and those older than 20 years. H influenzae serotype F cases increased in patients older than 60 years. Hib cases decreased in patients aged 1-5 months, 1-4 years, and older than 40 years, highlighting the success of Hib vaccination.[25]

In 2017, 2 cases of Hia infection were reported in Italy, and both were of the ST23 clone (previously only known to have been present outside Europe), which was concerning.[26] In the North America Arctic area, which includes Nunavik and Nunavut, Canada, and Alaska, invasive Hia isolates also belonged to the ST23 clonal complex.[27]

In Hungary, a single-center 14-year retrospective review of adults with invasive H influenzae infection showed an annual incidence of 0.1 cases per 100,000 inhabitants. NTHi strains were the most prevalent (79%), with 14% of all isolates exhibiting ampicillin resistance.[28]

Overall mortality from Hib meningitis is approximately 5%. Morbidity rates from meningitis, however, are high. If subtle neurologic changes are included, as many as 50% of individuals with Hib meningitis have some neurologic sequelae, including partial-to-total sensorineural hearing loss, developmental delay, language delay, behavioral abnormalities, language disorders, impaired vision, developmental disabilities, motor problems, ataxia, seizures, and hydrocephalus. Approximately 6% of individuals with Hib meningitis experience permanent sensorineural hearing loss. Epiglottitis carries a mortality rate of 5-10% (because of acute respiratory tract obstruction), and neonatal H influenzae disease carries a mortality rate of 55%.

A systematic analysis by the Global Burden of Disease Study 2019 revealed that from 1990 to 2019, H influenzae had the largest drop in mortality among children younger than 5 years (76·5% [69·5-81·8]) compared to S pneumoniae, N meningitidis, K pneumoniae and viruses.[29]

 

From the 1980s (prevaccine era) to 2005 (vaccine era), the incidence of vaccine-preventable invasive Hib disease decreased by ≥99.8%, and the associated mortality rate decreased by ≥99.5%.[30]  In parts of the world where the vaccine is not in regular use, morbidity and mortality rates of Hib disease remain high. 

Licensing of the Hib conjugate vaccine led to a substantial decline of Hib disease in the United States. In China, Hib immunization resulted to less Hib infection and more frequent reports of NTHi respiratory infections. NTHi has been isolated in 9.1% of 3,984 children with upper respiratory tract infection in China, with the highest carriage rate observed in the 3 to 4 year age group.[31]

Epidemiologic studies suggest that Hia infection occurs more in indigenous North American populations, with clinical presentation closely resembling that of Hib infection.[32]

In 2006, the Active Bacterial Core Surveillance Report estimated that, in the United States, 4800 cases (1.6 per 100,000 population) of invasive H influenzae infection occurred, resulting in 700 deaths (0.23 per 100,000 population).[17] In contrast, the latest Active Bacterial Core Surveillance Report for H influenzae infection in 2015 reported 6,100 (1.9 per 100,000) cases of invasive disease and 1,015 (0.32 per 100,000) deaths.[18]

Bacteremia and invasive disease associated with NTHi are becoming more prevalent and carry a significant mortality rate.[17] Increased NTHi cases can also be seen in patients with cancer, consistent with the changing H influenzae epidemiology in the rest of the population after the Hib vaccine was introduced.[33]  Because of Haemophilus influenzae serotype b (Hib) vaccination, non-Hib serotypes have emerged, including the incidence rate of Haemophilus influenzae serotype f (Hif) infection [estimated incidence rate of 0.15/100 000 population per year (range: 0.05-0.40/100 000), and a median case fatality ratio of 14.3 %].[34]

H influenzae is among the 3 most common bacteria isolated among patients with COVID19 infection, next to Mycoplasma pneumoniae and Pseudomonas aeruginosa. Nevertheless, only 7% of the 2,183 patients included in the review had bacterial co-infection, that is less than that observed in previous influenza pandemics. This finding does not support the routine use of antibiotics in patients with confirmed COVID19 infection. [35]

As mentioned, during the pandemic, there was a reduction in H influenzae cases in both the northern and southern hemispheres along with S pneumoniae and N meningitidis. Specifically, the relative risk of H influenzae invasive disease decreased by 49% from meta-analytic data. Unfortunately, cases from H influenzae, S pneumoniae and N meningitidis were increasing again towards the end of 2021.[13]

Transmission

H influenzae is recovered exclusively from humans, with no other known hosts.[36] It is a frequent colonizer of the nasopharynx and rarely is found in the genital tract. Infants and toddlers are considered to be reservoirs. Transmission occurs primarily by inhalation of droplets or direct contact with secretions. In neonates, transmission may occur with aspiration of amniotic fluid or contact with genital secretions.[37] NTHi frequently colonizes the lower respiratory tract of patients with COPD and cystic fibrosis.[36]

Outbreaks of H influenzae upper respiratory tract infection usually occur in crowded settings. Although H influenzae infections are common in the community, nosocomial outbreaks of upper respiratory tract infection have been reported. In a general hospital in western Japan, about 27 of 78 (34.6%) people developed respiratory symptoms during the 3-week period following admission of the index patient.[38] All isolates have a similar gel electrophoresis pattern, with beta-lactamase-negative ampicillin-resistant NTHi present in 13 individuals.

Race

The frequency of Hib disease is especially high in certain ethnic groups, including African Americans, American Indians (eg, Alaskan Eskimos, Navajo, Apache, Yakima, Athabaskan), and Australian Aborigines. Prior to availability of the Hib vaccine, the incidence of invasive disease was 10% higher in American Indians and Alaskan native children than the rest of the US population. The rate of Hib disease among rural Alaskan native children is high (5.4 per 100,000) despite Hib vaccination.[39]

In Queensland, Australia, the yearly incidence rate in all children younger than 5 years was 7.4 per 100,000, but the indigenous children (Aboriginal and Torres Strait Islander) of the same ages appeared to be more vulnerable, with an annual incidence rate of 10.2 per 100,000.[40]

Sex

Hib disease has no sexual predilection; however, women are at risk for postpartum sepsis, tuboovarian abscess, and chronic salpingitis caused by NTHi that colonize the genital tract.

Age

In general, Hib infections are rare in patients older than 6 years because of the acquisition of secondary immunity; however, immunocompromised individuals remain susceptible.

Hib meningitis primarily affects children younger than 2 years, with a peak frequency in infants aged 6-9 months. Epiglottitis is most common in children aged 2-7 years but can also occur in adults. Hib pneumonia typically occurs in children aged 4 months to 4 years. Hib causes septic arthritis and cellulitis in children younger than 2 years; before the conjugate vaccine became available, Hib was the leading cause of arthritis in this age group. Hib septic arthritis also occurs in adults. Prior to introduction of the Hib vaccine, Hib was the leading cause of occult bacteremia after Streptococcus pneumoniae in children aged 6-36 months. In the vaccine era, Hib occult bacteremia is rare. H influenzae otitis media can occur at any age but is most common in children aged 6 months to 6 years.

NTHi causes neonatal sepsis through vertical transmission via the female genital tract, maternal sepsis, and, infrequently, other invasive diseases. It also causes otitis media, sinusitis, bronchitis, and pneumonia in all age groups.

In 2006, the Active Bacterial Core Surveillance Report found that NTHi infection was most common among persons younger than one year and those aged 65 years or older, accounting for 6.5 and 4.3 cases per 100,000 general population, respectively.[17] By 2015, NTHi rates were 4.88 and 2.72 per 100,000 in the same age groups, respectively, although rates were highest in individuals aged 85 years and older, at 11.37 per 100,000.[18]

The prognosis of meningitis depends on age at presentation, duration of illness prior to antimicrobial therapy, CSF capsular polysaccharide concentration, and the rapidity with which it is cleared from the CSF, blood, and urine. Dexamethasone administered concurrently or shortly before the initial administration of antibiotics decreases the likelihood of hearing loss associated with Hib meningitis.

The prognosis of uncomplicated Hib pneumonia and nonencapsulated H influenzae infections usually is good.

Alert parents and caregivers of the index patient that if any exposure to the index patient has occurred within a childcare setting to seek prompt medical care for any signs or symptoms that may be related to Hib infection.

For excellent patient education resources, visit eMedicineHealth's Cold and Flu Center. Also, see eMedicineHealth's patient education articles Sepsis (Blood Infection); Immunization Schedule, Children; and Flu in Children.

Meningitis

Meningitis is the most serious manifestation of H influenzae type b (Hib) infection. Symptoms of antecedent URTI are common. Altered mental status and fever are the most common presenting features. Headache and photophobia are usually present in older children.

Symptoms related to other infectious foci (eg, cellulitis, arthritis, pneumonia) are encountered in 10-20% of children. Infants have nonspecific symptoms, including irritability, fever, lethargy, poor feeding, and vomiting.

H influenzae accounts for 5-10% cases of adult meningitis, and patients can present with at least one of the classic triad of fever, neck stiffness, and altered mental status.

Cellulitis

The buccal and periorbital regions are most commonly involved with associated fever. Orbital cellulitis is uncommon and tends to be a complication of ethmoid or sphenoid sinusitis.

Epiglottitis

Patients with H influenzae epiglottitis may have respiratory difficulty (78%), sore throat (65%), history of fever (57%), difficulty swallowing (49%), drooling (42%), change in voice (33%) and cough (19%).[41]

Pneumonia

H influenzae pneumonia is clinically indistinguishable from other bacterial pneumonias, but insidious onset and a history of fever, cough, and purulent sputum production are usually noted.

H influenzae was shown to be more common as a cause of community-acquired pneumonia (CAP) in patients with previous pneumococcal vaccination and those with respiratory co-morbidities.[42]

Pericarditis

Patients with Hib pericarditis present with a history of fever, respiratory distress, and tachycardia.

Septic arthritis

Patients with H influenzae septic arthritis note joint pain, swelling, and decreased mobility.

Occult bacteremia

Fever, anorexia, and lethargy occur in persons with occult bacteremia.

Underlying medical conditions

Pulmonary disease, HIV infection (and other immunodeficiency states), alcoholism, pregnancy, and malignancy may predominate in adults with invasive Hib disease.

Patients with primary ciliary dyskinesia, an inherited condition with motile cilia dysfunction, have been shown to grow H influenzae from sputum and nasal lavage. More recently, these same patients appear to be susceptible to the development of NTHi biofilm, as seen in both culture and confocal and scanning microscopy.[43, 44]

NTHi is considered a common commensal in the nasopharynx, but when it reaches the lower respiratory tree in patients with COPD, it is associated with significant inflammation that generally leads to morbidity due to worsening symptoms and more frequent COPD exacerbations.[45, 46]

Neonatal infections

Neonates with H influenzae disease present within 24 hours of birth; these infections are caused by NTHi strains, which colonize the maternal genital tract.

Premature birth, premature rupture of membranes, low birth weight, and maternal chorioamnionitis are associated with H influenzae disease.

Manifestations may be nonspecific and may include those of bacteremia, sepsis, meningitis, pneumonia, respiratory distress, scalp abscess, conjunctivitis, and vesicular eruption.

NTHi is a major cause of pneumonia in infants in developing countries.

Nonencapsulated H influenzae infections

Nonencapsulated H influenzae commonly causes various mucosal infections, including otitis media and conjunctivitis.

S pneumoniae and nonencapsulated H influenzae are the most common causes of otitis media, which manifests in infants as fever and irritability and in older patients as ear pain. Frequently, a history of URTI exists.

NTHi is a major cause of conjunctivitis in older children and can cause outbreaks, especially in daycare centers. After S pneumoniae, NTHi is the most common cause of community-acquired bacterial pneumonia in adults. It is common in patients with COPD and HIV disease and exacerbates COPD, symptoms of which include low-grade fever, increased cough and sputum production, and dyspnea. NTHi invasive disease is frequently associated with underlying medical conditions, including prematurity, advanced age, alcoholism, malignancy, CF, asthma, cerebrospinal fluid (CSF) leak, CNS shunts, congenital heart disease, and immunoglobulin deficiency.

Meningitis

Clinical manifestations of Hib meningitis are indistinguishable from other causes of bacterial meningitis.

The usual presentation consists of a few days of mild illness followed by ominous deterioration.

Altered mental status and fever are the most common findings.

Seizures and coma develop as the disease progresses.

Children may have few specific signs. Nuchal rigidity is often absent in children younger than 18 months. In infants, the disease course may be fulminant, with death occurring within a few hours.

Consider the possibility of subdural effusion, a common complication of Hib meningitis, in a patient who has been treated for 3 days with appropriate antibiotics and has experienced a tense anterior fontanelle, seizures (especially if focal), hemiparesis, or altered CNS function.

Cellulitis

The clinical features are fever and a raised, indurated, tender area with indistinct margins mostly on the head and neck, particularly the buccal and preseptal areas. This is often caused by contiguous sinus disease. The indurated area may progress to a violaceous hue, although this is not specific to Hib.

Orbital cellulitis may occur and is distinguished from periorbital cellulitis based on the presence of proptosis, chemosis, impaired vision, limitation of extraocular movements, and pain with eye movement. A secondary focus of infection, including meningitis, is evident in 10-15% of patients with orbital cellulitis.

Epiglottitis

Clinical manifestations in children include a toxic anxious appearance, progressive respiratory difficulty, and the inability to swallow secretions while sitting in the tripod position (ie, sitting with arms back, trunk leaning forward, neck hyperextended and chin forward in an attempt to open the airway fully).

Physical examination findings include change in voice (90%), stridor (81%), neck tenderness (65%), pharyngitis (61%), and adenopathy (39%).[41]

Pneumonia

H influenzae pneumonia (whether Hib or NTHi) is clinically indistinguishable from other bacterial pneumonias.

Pericarditis

The individual is acutely ill with fever and respiratory distress.

Septic arthritis

Hib septic arthritis affects single large joints (eg, knee, ankle, hip, elbow).

Symptoms, usually preceded by a URTI, include decreased range of motion, erythema, and warmth and swelling in affected joints, in addition to fever.

In adults, joint involvement can be monoarticular or polyarticular.

Extra-articular sites of infection, including those associated with meningitis, pneumonia, cellulitis, and sinusitis, may also be evident.

Occult bacteremia

Occult bacteremia is characterized by fever (temperature >39°C) with no obvious focus of infection. About 30-50% of patients have focal infections.

Other

Nonencapsulated H influenzae infections can manifest in various mucosal infections (eg, otitis media, conjunctivitis, sinusitis, bronchitis). An otitis media diagnosis is confirmed with pneumatic otoscopy. Conjunctivitis usually is bilateral and characterized by conjunctival hyperemia and purulent eye discharge.

NTHi strains can cause postpartum sepsis with ​endometritis, tuboovarian abscess, and chronic salpingitis.

Signs of invasive disease in neonates include sepsis, pneumonia, conjunctivitis, respiratory distress syndrome, scalp abscess, cellulitis, meningitis, congenital vesicular eruption, mastoiditis, and septic arthritis.

Bacteremia precedes Hib meningitis and other invasive Hib diseases. Direct extension of infection from the sinuses or ears is rare. The magnitude and duration of bacteremia are the primary determinants of CNS invasion, which occurs via the choroid plexus. The magnitude of the CSF bacterial density correlates with the severity of the disease. Morbidity and mortality associated with meningitis result from inflammation, edema, and increased CSF pressure. Brain parenchymal invasion is rare.

In epiglottitis, Hib invades the epiglottis and supraglottic tissues, causing cellulitis and swelling that causes the epiglottis to curl posteriorly and inferiorly over the airway, thus obstructing airflow during inspiration but allowing normal expiration. An acute airway obstruction follows.

Invasive H influenzae disease in neonates is rare and is caused most often by NTHi strains. This condition is associated with premature birth, premature rupture of membranes, low birth weight, and maternal chorioamnionitis. Transmission occurs through the maternal genital tract. NTHi biotype 4 can colonize the genital tract and is a major cause of invasive disease.

Complications of meningitis include seizures, cerebral edema, subdural effusion or empyema, inappropriate secretion of antidiuretic hormone syndrome, cortical infarction, cerebritis, intracerebral abscess, hydrocephalus, and cerebral herniation. Protracted fever is not uncommon, with approximately 10% of children remaining febrile for at least 10 days.

Complications of orbital cellulitis include subperiosteal or orbital abscesses.

Complications of pneumonia include empyema and pericarditis.

Complications of otitis and sinusitis include mastoiditis and parameningeal abscess.

Gram stain

Test results on body fluids from various sites of infection that reveal small, gram-negative, pleomorphic coccobacilli with polymorphonuclear cells are strong evidence of infection.

Bacterial culture

Detection of the organism in a blood culture or any other body fluid is the most confirmatory method of establishing the diagnosis. Optimal growth requires the use of chocolate agar and BVCCA, which is a selective media of chocolate agar that contains bacitracin, vancomycin, and clindamycin. BVCCA has been found superior to chocolate agar for isolation of NTHi from nasopharyngeal swabs.[47] Some H influenzae strains grow best in 5-10% carbon dioxide.[36]

The viability of H influenzae is lost rapidly, so clinical specimens should be inoculated to an appropriate culture media without delay.[36]

Seventy to 90% of patients with epiglottitis have positive blood culture results. However, to avoid laryngospasm, perform venipuncture and cultures of the inflamed epiglottitis only after the airway has been secured.

Serotyping

Slide agglutination with type-specific antisera is used for serotyping H influenzae. In one study, molecular typing with PCR was found to be more accurate than slide agglutination serotyping.[48]

Immunologic studies

Detection of the PRP polysaccharide capsule via countercurrent immunoelectrophoresis, latex particle agglutination, co-agglutination, and enzyme-linked immunosorbent assay is an important adjunct to culturing in establishing a rapid diagnosis.

Even if antibiotics were previously administered, the diagnosis can be confirmed based on the detection of the polysaccharide capsule in body fluids, including serum, CSF, urine, and pleural, pericardial, and articular fluid. False-positive results in CSF are rare but occur with serum or urine because of nonspecific agglutination and antigenic cross-reactivity with other bacteria.

CSF features

In meningitis, the CSF examination demonstrates pleocytosis (mean, 4000-5000 WBCs/µL) with a predominance of neutrophils.

Decreased CSF glucose levels are encountered in 75% of patients, increased CSF protein levels and detectable capsular antigen in 90%, and a positive CSF Gram stain result in 80%.

Prior antibiotic treatment significantly decreases the H influenzae type b (Hib) concentration in the CSF and decreases the sensitivity of the Gram stain; however, antibiotics do not substantially affect the total CSF blood cell count, differential, chemistries, and presence of the PRP capsule in pretreated patients.

Blood cell counts

Perform blood cell counts for anemia, leukocytosis, and thrombocytosis or thrombocytopenia.

Acute phase reactants

Elevated erythrocyte sedimentation rates (ESRs) and C-reactive protein levels are characteristically observed in patients with septic arthritis.

Nucleic acid amplification tests

Nucleic acid amplification diagnostics offer a rapid and accurate method of diagnosing microbial pathogens. Compared with conventional microbiological approaches, real-time PCR (rtPCR) has been shown to accurately differentiate NTHi from Haemophilus haemolyticus, a closely related species that is generally considered to be nonpathogenic.[49] Given the fastidious nature of H influenzae, PCR also has the advantage of detecting nonviable pathogens, especially among patients with previous antibiotic exposure. PCR-based methods are frequently used worldwide and are becoming the diagnostic method of choice in various clinical settings.

For H influenzae infection, PCR is more accurate than conventional methods of serotyping (slide agglutination method). The diagnostic sensitivity for Hib is 72-92%.[37]

In patients with pneumonia who are unable to provide lower respiratory tract samples, rtPCR of upper respiratory tract samples yields a sensitivity, specificity, PPV, and NPV of 75%, 80%, 45%, 94%, respectively, for H influenzae.[50]

Multiplex PCR and line probe assay

Multiplex PCR assay enables simultaneous detection of multiple pathogens, reducing analysis time and cost. It has been used for the diagnosis of multiple viral and bacterial pathogens, including H influenzae. Multiplex PCR assays are commonly used to evaluate CNS and respiratory tract infections.

Several in-house and commercial PCR-based assays have been described for the detection of meningitis caused by S pneumoniae, Neisseria meningitidis, and H influenzae. Sensitivity and specificity for detection of bacterial pathogens are high, ranging from 92.8-100% and 95.1-97.2%, respectively.[51, 52, 53]  A study looked at using real-time polymerase chain reaction (RT-PCR) of cerebrospinal fluid (CSF) as a rapid diagnostic test for bacterial meningitis and compared these with bacterial culture, and showed that sensitivity and specificity for RT-PCR were 100% and 95.46%, respectively. This becomes useful when antibacterial treatment was given before clinical samples were taken.[54]

For pneumonia, sensitivity (90%) and specificity (65%) are lower.[55] Nevertheless, multiplex PCR achieved greater pathogen detection(87%), roughly double that detected by culture-based methods (39%), even after antimicrobial administration (78% vs 32%).[56]  A 2023 study evaluating the clinical relevance of the Biofire©FilmArray pneumonia panel among hospitalized patients was done; the detection rate of Haemophilus influenzae (along with Staphylococcus aureus, and Moraxella catarrhalis) was high but not associated with pneumonia, and was much higher from bronchoalveolar lavage specimens. Further evaluation in randomized controlled trials was recommended.[57]

A line probe assay (LPA) that is based on multiplex PCR followed by reverse hybridization using sequence-specific oligonucleotide probes has been developed for the detection of bacterial pathogens that cause meningitis, specifically H influenzae, S pneumoniae, and N meningitidis.[58] Compared with standard PCR as reference, the overall sensitivity and specificity of LPA for the detection of bacterial pathogens were 76% and 88%, respectively. For Hib, LPA sensitivity and specificity were 88% and 96%.

A novel technology (VAPChip assay) currently under development combines bacterial species identification and detection of resistance genes associated with beta-lactam resistance encoding carbapenemases, extended-spectrum beta-lactamases, and penicillin-binding protein 2a. It was designed to detect nosocomial pneumonia pathogens, including H influenzae. The VAPChip system showed sensitivity and specificity of 72.9% and 99.1%, respectively, for the identification of respiratory pathogens. Detection of resistance genes, however, needs improvement.[59]

Isothermal NAT

Because PCR testing requires expensive thermocycler equipment and a skilled operator, it cannot be used as a point-of-care test or in resource-limited settings. Isothermal nucleic acid amplification methods provide a cheaper alternative to PCR, as they do not require thermocycler equipment. Duplex recombinase polymerase amplification (RPA) is a novel isothermal NAT method used to detect pathogens that cause meningitis, specifically H influenzae, S pneumoniae, and N meningitidis.[60] It exhibited 100% sensitivity and 100% specificity for the diagnosis of H influenzae meningitis.

Proteomic profiling

Proteomic profiling via matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is an alternative to biochemical and molecular methods of species identification. Studies have shown that MALDI-TOF MS accurately differentiates between NTHi and H haemophilus, a respiratory tract commensal.[61, 62] Apart from species identification, the sensitivity and specificity of MALDI-TOF MS for capsule typing was found to be 100% and 92.2%, respectively.[63] In another study, the sensitivity and specificity for identification of type b, type e, and type f capsular serotypes and NTHi were 100% and 94.3%, 94.7% and 97.9%, 97.4% and 97.9%, and 85.5% and 99.2%, respectively.[64] MALDI-TOF MS is quicker to perform than PCR and conventional serotyping (slide agglutination) methods and has a lower cost per sample, making it a useful tool for H influenzae surveillance and outbreak investigations.

Whole-genome–sequencing–based tools

Whole–genome–sequencing (WGS)–based tools identify species by comparing sample genomes against a reference collection of representative genomes. Owing to long computational runtime, WGS-based tools once were considered impractical for routine clinical use. An innovation that addressed this limitation was developed in BMScan,[65] which allows rapid and accurate identification of bacterial meningitis pathogens, including H influenzae and related species, N meningitidis and related species, S pneumoniae, Listeria monocytogenes, and Escherichia coli. Topaz et al demonstrated that BMScan accurately identified 99.97% of species of interest within an average of 16 minutes and 47 seconds, meaning it has potential for clinical use. This is a proof-of-concept study that can be extended to other pathogens and clinical settings. In the future, this could lead to transition from the traditional phenotypic detection method to genome–sequencing–based methods of identification.

CT scanning

In meningitis, a CT scan of the head is not required routinely.

In infants and children with suspected bacterial meningitis, CT scanning of the head is recommended before lumbar puncture in patients with the following[6] :

• Immunocompromise
• History of selected CNS disease, particularly those with CSF shunts, hydrocephalus, space-occupying lesions, history of trauma, post-neurosurgery
• Papilledema
• Selected focal neurologic deficits, but not cranial nerve palsy of VI or VII
• Delayed diagnostic lumbar puncture

In adults with suspected bacterial meningitis, CT scanning is recommended before lumbar puncture in patients with the following[6] :

• Immunocompromise
• History of CNS disease
• Newly onset seizure
• Papilledema
• Altered consciousness
• Focal neurologic deficit
• Delayed diagnostic lumbar puncture

In addition, a head CT scan may help identify subdural effusion.

In patients with orbital cellulitis, a CT scan of the head is useful in delineating the extent of the lesion.

Chest radiography

Patients with Hib pneumonias tend to have more pleural and pericardial involvement (50% of patients) than those with other bacterial pneumonias.

Community-acquired pneumonias due to NTHi are characterized by alveolar infiltrates in patchy or lobar distributions.

Lateral neck radiography

In epiglottitis, a lateral neck radiograph reveals dilatation of the hypopharynx and a swollen epiglottis (termed the thumbprint sign). In addition, the cervical spine is usually straightened.

If epiglottitis is clinically suspected, obtain radiography only if a functional airway is guaranteed.

Echocardiography

Obtain echocardiography when pericarditis is suspected.

In patients with cellulitis, direct aspiration of the soft tissue or aspiration after injecting the subcutaneous tissue with sterile nonbacteriostatic solution can be used to detect the organisms via Gram stain and culture.

Perform a lumbar puncture when meningitis is suspected. CT scanning should be performed prior to lumbar puncture in certain cases (see Imaging Studies).

The following invasive procedures can be used to obtain appropriate fluid and to establish an etiologic diagnosis:

• Bronchoscopy
• Joint, lung, sinus, and soft-tissue aspiration
• Transtracheal aspiration
• Tympanocentesis
• Pericardiocentesis

In women, obtain tubal cultures via laparoscopy and peritoneal fluid cultures by culdocentesis for NTHi.

In patients with epiglottitis, use endotracheal intubation or tracheostomy to secure an airway.

Antibiotics and supportive care

Antibiotics and supportive care are the mainstays of treatment for Haemophilus influenza infections.

Initially, invasive and serious H influenzae type b (Hib) infections are best treated with an intravenous third-generation cephalosporin until antibiotic sensitivities become available. In Malawi, Africa, intramuscular ceftriaxone was compared with intravenous ceftriaxone and was not found to increase the mortality rate. This may be important in developing countries where the intravenous route may not be possible.[66]

It is important to monitor the resistance rates of H influenzae to different antibiotics to guide empiric antimicrobial choices while awaiting susceptibility results. For instance, a study of 117 H influenzae isolates in Poland showed that susceptibilities to ampicillin and amoxicillin were below 80%, susceptibility to cefuroxime was just slightly above 80%, whereas susceptibilities to amoxicillin/clavulanate and ceftriaxone were close or equal to 100%,[67] making the latter 2 more reliable for empiric treatment in that locality.

Among 610 respiratory and vaginal isolates from pediatric patients in China, 51.5% were beta-lactamase–positive; 52.5% of isolates were resistance to ampicillin. The rates of susceptibility to ampicillin/sulbactam, cefotaxime, cefuroxime, clarithromycin, and sulfamethoxazole-trimethoprim were 95.9%, 96.4%, 72.1%, 81.8%, and 36.4%, respectively,[68] meaning that ampicillin/sulbactam and cefotaxime should be the primary choices for empiric treatment.

In a UK study, among 24 sputum specimens from patients with COPD that were positive for H influenzae, 67% were resistant to ampicillin (of which 56% were beta-lactamase–positive), 46% were resistant to erythromycin, and 0% were resistant to fluoroquinolones.[69]

In Canada from 2007-2014, NTHi comprised 54.6% of H influenzae isolates, and the 45.4% that were serotypeable were mostly Hia (23.1%), followed by Hib (8.3%), and type f (10.8%). The resistance rate to ampicillin was 16.4%, and the percentage of beta-lactamase–producing isolates increased from 13.5% in 2007-2010 to 19% in 2011-2014. No resistance to third-generation cephalosporins and fluoroquinolones was observed, but resistance to trimethoprim/sulfamethoxazole was common.[70]

A study from Thailand’s largest national tertiary referral center collected 1126 H influenzae clinical isolates (sputum, adenoid tissue, bronchoalveolar lavage fluid) from patients ranging in age from 7 days to 96 years from October 2007 to June 2016. Almost all isolates were susceptible to amoxicillin/clavulanate, cefotaxime, ceftriaxone, cefuroxime, and ciprofloxacin, whereas the susceptibility rate to trimethoprim/sulfamethoxazole was only 50.1%, and more than 38% of isolates were resistant to ampicillin.[71]

In one Japanese study, most H influenzae isolates collected from patients with acute urethritis and/or epididymitis were susceptible to ceftriaxone, fluoroquinolones, macrolides, and tetracyclines, based on the recommended MIC breakpoints (Clinical and Laboratory Standards Institute). However, azithromycin treatment failures were noted in acute urethritis cases despite reports of azithromycin susceptibility.[72]

Another concerning finding from Japan is the prevalence of beta-lactamase–negative but ampicillin-resistant H influenzae isolates that are also macrolide resistant.[73]  Strains of BLNAR H influenzae increased significantly from 2013 to 2016 and tend to show multidrug resistance. It accounted to more than 50% of isolates in 2014, eventually reaching 60% in 2016.[74]

In Taiwan, the incidence of single-drug resistance, MDR, and XDR H influenzae from 2007 to 2018 were 21.5% (450/2091), 26.6% (557/2091), and 2.5% (52/2091), respectively.[75]   About 7.7% of the XDR strains have been isolated from blood cultures, and were not linked to hospital-acquired infections. Nonetheless, these XDR strains were found to be susceptible to cefotaxime. In another multicenter study in Taiwan, levofloxacin resistance was reported in 24.3% of H influenzae isolates in 2010; all bearing gyrA and parC mutations.[76]  Nasopharyngeal colonization with fluoroquinolone resistant H influenzae has also been reported in 40% of 48 nursing home residents.[77]

Surveillance of Antibiotic Resistance (SOAR) from 2015 to 2017 in Argentina, Chile, Costa Rica, and 2016 to 2017 in Ukraine show high antibiotic susceptibility of H influenzae.[78, 79]  In Tunisia, H influenzae isolates were susceptible to most antibiotics except ampicillin and amoxicillin (33.8% b-lactamase positive), trimethoprim/sulfamethoxazole (51.4–56.8%), cefaclor (1.4%), cefuroxime (4.1%), macrolides (1.4–2.7%) and cefdinir (66.2%).[80]

Because of the emerging resistance of H influenzae and other bacteria to commonly used antibiotics, the use of alternative drug therapies has been explored. In vitro studies revealed that H influenzae is susceptible to ceftaroline [81]  and ceftolozane tazobactam.[82]  In 2017, the WHO published its first ever list of antibiotic-resistant "priority pathogens," which included 12 families of bacteria that posed "the greatest threat to human health". In the WHO priority pathogens list for research and development of new antibiotics, ampicillin-resistant Haemophilus influenzae was included in Priority Group 3 (along with penicillin-non-susceptible Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae and  fluoroquinolone-resistant Shigella spp.[83]

The site of infection and the clinical response determine the length of antibiotic treatment.

Meningitis

Administer parenteral antibiotics (eg, ceftriaxone, ceftazidime, cefotaxime, ampicillin-sulbactam, fluoroquinolones, azithromycin) to patients with meningitis for 7 days. Third-generation cephalosporins (cefotaxime and ceftriaxone) are the initial drugs of choice for suspected Hib meningitis.

Once the susceptibilities are known, adjust antibiotics accordingly.

For beta-lactamase–positive H influenzae meningitis, the recommended standard antibiotic is a third-generation cephalosporin. Alternative antimicrobials include cefepime, chloramphenicol, and fluoroquinolones. For beta-lactamase–negative H influenzae meningitis, the recommended standard antimicrobial is ampicillin, while any of those mentioned for beta-lactamase–positive H influenzae meningitis may be used as an alternative.[6]

Do not use ampicillin empirically, since as many as 80% of global isolates are resistant, usually because of plasmid-mediated beta-lactamase production.[84, 85, 86, 87, 88, 89, 90]

Cefuroxime is not recommended, because delayed sterilization is more common.

Chloramphenicol produces adequate bactericidal blood and CSF levels but is used infrequently because it requires monitoring of drug levels and can result in dose-dependent (though reversible) bone marrow toxicity (particularly in neonates and patients with liver disease) or an idiosyncratic aplastic anemia.

Dexamethasone is an important adjunctive treatment in patients with meningitis who are older than 2 months because it has been shown to decrease the inflammatory response and the rate of hearing loss[91] and other neurologic complications.[92]

The 2004 Infectious Disease Society of America (IDSA) guidelines recommend that dexamethasone 0.15 mg/kg/d q6h for 2-4 days be administered to children (but not adults) with H influenzae meningitis. When steroids are used, they must be administered either prior to or along with antibiotics, as dexamethasone administered after antimicrobials is unlikely to be beneficial.[93]

In January 2007, a systematic review of randomized controlled trials involving adjuvant corticosteroids therapy in acute bacterial meningitis found a significant benefit in children from developed countries but no beneficial or harmful effects in children in developing countries. This meta-analysis also found that dexamethasone administered to adults with community-acquired meningitis (including that caused by H influenzae) decreased the risk for mortality and neurologic sequelae. Based on data from 18 randomized controlled trials, the authors concluded that all adults and children with acute bacterial meningitis in developed countries who have good access to medical care should receive adjuvant corticosteroids. The authors also found no significant increase in adverse effects due to corticosteroids. The recommended dose for dexamethasone in adults and children is 0.6 mg/kg/d for 4 days.[91]

A systematic review of 25 randomized controlled trials in 2015 showed that, in the treatment of Hib meningitis, corticosteroids were associated with a nonsignificant reduction in mortality, but a significant reduction in severe hearing loss and neurologic sequelae. However, this benefit was found only in high-income countries but not in low-income countries.[94]

A retrospective study of 425 patients in Ethiopia showed that the use of dexamethasone was significantly associated with increased mortality. However, in this study, acute bacterial meningitis was diagnosed based on clinical presentation. Lumbar puncture was performed in only 56% of patients, and only 19% had CSF findings compatible with bacterial meningitis. This study shows that there are potential deleterious effects to steroid therapy in unconfirmed cases, which can be reflective of low-income settings.[95]

A 2015 meta-analysis assessed the effectiveness and safety of corticosteroids in reducing death and neurologic sequelae in neonates with bacterial meningitis. Two studies were included, one of poor quality. Results suggested a reduction in mortality and hearing loss.[96]

A randomized prospective study in 1994 found that, in treatment for bacterial meningitis, a 2-day course of dexamethasone provided effectiveness similar to that of a 4-day course.[97] However, most studies recommend a 4-day dexamethasone course.

In November 2007, a prospective randomized double-blind placebo-controlled trial studied adjuvant glycerol and dexamethasone in children with bacterial meningitis. All patients were given ceftriaxone and randomized to receive intravenous dexamethasone, oral glycerol, both agents, or neither agent. In addition, a subgroup of patients with Hib meningitis was studied. Findings showed that glycerol, an inexpensive osmotic diuretic that can be administered orally, reduced the incidence of neurologic sequelae and death. Dexamethasone prevented profound hearing loss when the timing of dexamethasone and ceftriaxone administration was not taken into account. Few adverse effects were found with either adjuvant medication. Additional studies need to be performed to evaluate the impact of glycerol in bacterial meningitis.[98, 99]

In 2011, however, a double-blind randomized controlled trial of adjuvant glycerol in adult bacterial meningitis in Malawi showed no difference in mortality and neurologic sequelae. Possible reasons for the conflicting results could be that the dose used in this study was higher than that used by Peltola et al.[99]  In addition, adjuvant glycerol was given for 4 days compared with 2 days. The population in this study had a high HIV seroprevalence.[100, 101]

In 2007, a Vietnamese study evaluated the benefit of dexamethasone in adults and adolescents with confirmed or suspected bacterial meningitis. Overall, initial findings showed that dexamethasone did not decrease the mortality rate at 1 month or the incidence of mortality or disability at 6 months. However, when the results were compared with culture-proven disease, dexamethasone was found to confer a significant benefit in terms of both mortality and disability in patients with confirmed bacterial meningitis. Among the patients studied, only 7 had H influenzae meningitis, and 6 of these were in the placebo group.[102]

In a 2007 study in Malawi, Africa, dexamethasone was given to adults with bacterial meningitis but was not found to reduce mortality or morbidity. However, 90% of the study patients had HIV infection. Of the 465 patients studied in this group, only 3 had H influenzae meningitis.[66]

Treatment of H influenzae meningitis also includes ongoing supportive care and management of complications such as shock, inappropriate secretion of antidiuretic hormone syndrome, seizures, subdural empyema, and secondary foci of infection.

Small, clinically insignificant subdural effusions are common.

In uncomplicated cases, a repeat lumbar puncture is unnecessary to ensure sterility of the CSF.

Cellulitis

In patients with Hib cellulitis, administer parenteral antibiotics until the patient shows defervescence and the cellulitis subsides. Then, administer appropriate oral antibiotics until the course of therapy, usually 7-10 days, is finished. Empiric therapy for preseptal cellulitis should cover not only Hib but also S pneumoniae, Staphylococcus aureus, and group A beta-hemolytic streptococci. Hib once was one of the most common pathogens in preseptal and orbital cellulitis in children before the Hib vaccine became widely administered.[103]

Patients with orbital cellulitis should receive at least 14 days of inpatient parenteral therapy. Upon hospital discharge, the intravenous antibiotic should be switched to oral (eg, amoxicillin-clavulanate) and continued for an additional 1-3 weeks.[104]

Surgical drainage may be needed for the underlying sinusitis or for orbital abscesses.

Epiglottitis

Maintenance of a patent airway via intubation or tracheostomy is the mainstay of treatment for epiglottitis.

If a patient presents with evidence of respiratory compromise, the following steps should be taken[105] :

• Administer oxygen support via face mask (eg, 60%).
• Consult with an otorhinolaryngologist or anesthesiologist so that the patient's airway can be secured either via intubation or creation of a surgical airway.
• If feasible, bring the patient to the operating room to secure and assess the airway and to swab the epiglottis. Heliox and 4 mL of nebulized 1:1,000 epinephrine may be administered for airway improvement to facilitate transfer.
• Administer intravenous dexamethasone (eg, approximately 4 mg every 6 hours).

Intravenous ceftriaxone 2 g once daily (after blood culture specimens have been drawn) is recommended until the patient is clinically well and able to swallow; afterward, it can be switched to an oral equivalent (eg, amoxicillin/clavulanate 625 mg thrice daily), although culture and susceptibility results must be taken into consideration. The total antimicrobial treatment course should be 7 days (up to 10 days). In patients with penicillin anaphylaxis and/or severe allergies to cephalosporins, intravenous vancomycin plus ciprofloxacin parenterally 400 mg every 12 hours is the recommended regimen. Once the patient is clinically well, the said regimen should be switched to a fluoroquinolone to complete a total course of 7 days (up to 10 days).[105, 106]

Arthritis

A short course of intravenous antibacterial therapy followed by an oral agent for 2-3 weeks is considered safe and effective in uncomplicated cases. However, intravenous antimicrobial treatment should be given for at least 3 weeks if the septic arthritis is more complicated.[107]

Therapy may continue beyond 3 weeks until the ESR begins to normalize. The ESR may lag behind successful clinical response for weeks; accordingly, the C-reactive protein test may be a more useful laboratory tool because its values tend to normalize more rapidly.

Evidence has shown that high doses of well-absorbed antibacterials for 10 days (given intravenously for a only a couple of days) appear noninferior to 30 days of treatment for childhood septic arthritis, but only if the patient responds well clinically and the CRP level promptly normalizes.[108] Because of this, attempting a short course of therapy (10 days) has been recommended (1) if the patient (or parent) will be compliant and amenable to close clinical, laboratory, and radiographic follow-up and (2) if the patient (or parent) is willing to prolong the antimicrobial course for more than 10 days if symptoms and CRP levels persist. If any of the above conditions are in question, the longer treatment course is prudent to reduce the likelihood of treatment failure (around 10%, which can seriously affect the patient's quality of life).[109]

Bacteremia and other Hib infections

Bacteremia precedes essentially all invasive Hib infection.

Approximately 30-50% of children with occult Hib bacteremia (bacteremia without an identifiable cause) develop a focus of infection such as meningitis, cellulitis, or pneumonia. Therefore, reevaluate these children (including with lumbar punctures and chest radiography) for an infectious focus and obtain repeat blood cultures.

Administer parenteral antibiotics for at least 2-5 days and guide subsequent therapy based on the focus of infection. If no focus is identified, substitute oral antibiotics to complete 7-14 days of therapy, as in other gram-negative bloodstream infections/bacteremias.

Studies have been conducted to determine the optimal treatment duration for gram-negative bacteremia. It has been reported that 7 days (or even less) of antibacterial treatment for gram-negative bacteremia results in similar clinical response rates and microbiological cure rates when compared with treatment durations of 8-14 days and more than 14 days.[110]

A retrospective study of uncomplicated gram-negative bacteremia in children showed that antibiotic treatment for more than 10 days did not decrease the risk for treatment failure compared to shorter therapy and may increase the risk for candidemia.[111]

In contrast, a newer study on uncomplicated gram-negative bacteremia concluded that there was an increased risk for treatment failure in patients given antibiotic therapy for just 7-10 days compared with those who were treated for more than 10 days, supporting the traditional 2 weeks of treatment. Additional risk factors identified for treatment failure included liver cirrhosis and immune compromise. Definitive antibacterial treatment with intravenous or highly bioavailable oral agents decreased the risk for treatment failure.[112]

International guidelines for the management of sepsis and septic shock published by Rhodes et al in 2017 still suggest 7-10 days of antibacterial treatment "for most serious infections associated with sepsis and septic shock," which would include bacteremias. However, the authors labelled it as a weak recommendation based on low quality of evidence.[113]

Patients with pericarditis, empyema, endocarditis, endophthalmitis, or osteomyelitis require antibiotic treatment durations specific to the condition (and not the bacterial pathogen).

Nonencapsulated H influenzae

These organisms can cause mucosal infections treatable with oral antibiotics. The first-line antibiotic for otitis media is high-dose amoxicillin (80-90 mg/kg/day in 2 divided doses) because it is safe, inexpensive, and palatable and covers a narrow microbiologic spectrum. Amoxicillin-clavulanate (amoxicillin 90 mg/kg/day, with clavulanate 6.4 mg/kg/day in 2 divided doses) is recommended in patients who have received amoxicillin in the preceding 30 days, patients with coexisting conjunctivitis, or patients with otitis media due to beta-lactamase–positive H influenzae.[114] Penicillin-allergic individuals may be treated with erythromycin-sulfisoxazole or cefaclor. Cefaclor has weak activity against beta-lactamase–producing bacteria and causes a serum sickness–like illness in 2% of patients. Approximately 25-50% of NTHi strains produce beta-lactamase and, therefore, are resistant to amoxicillin and ampicillin.

Oral antibiotics with activity against beta-lactamase–producing H influenzae include trimethoprim-sulfamethoxazole, cefuroxime axetil, cefixime, clarithromycin, azithromycin, and fluoroquinolones. Patients with conjunctivitis should receive topical antibiotics such as sulfacetamide and erythromycin.

In children younger than 2 years and in children with severe symptoms, the standard 10-day antibiotic course is recommended. In children aged 2-5 years who have mild to moderate acute otitis media, 7 days of oral antibiotic therapy is recommended. In children aged 6 years or older who have mild to moderate symptoms, 5-7 days of antibacterial therapy is considered adequate.[114]

The recommended duration of antimicrobial treatment for uncomplicated acute bacterial rhinosinusitis in adults is 5-7 days, while, in children, the recommended course of therapy is still 10-14 days.[115]

Administer parenteral antibiotics to patients with invasive NTHi infection, which can be treated similarly to invasive Hib disease.

Andrographalide is being evaluated for its potential in preventing lung inflammation due to NTHi infection, especially in cigarette smokers.[46]

Patients with subdural and pleural empyema may require surgical drainage if orbital cellulitis is extensive.

Patients with pericarditis require systemic antibiotics and drainage via early pericardectomy or pericardiostomy rather than multiple pericardiocentesis.

Patients with septic arthritis of the hip require surgical drainage to avoid avascular necrosis of the femoral head. Repeated aspirations or surgical drain placement may be needed in other infected joints to reduce pressure.

Consult an ear, nose, and throat specialist and an anesthesiologist for help in securing difficult airways in all cases of suspected epiglottitis.

Consult a neurosurgeon for suppurative complications of nervous system involvement.

Consult an ophthalmologist for management of orbital cellulitis.

Consult an infectious disease specialist for assistance with complicated infections.

Consult an orthopedic surgeon for surgical drainage of a joint.

The highly effective Hib conjugate vaccine, routinely administered to infants and children, has dramatically reduced the prevalence of invasive Hib disease.[116] The vaccine elicits a protective antibody and prevents disease by reducing pharyngeal colonization with Hib.

Conversely, there is limited evidence on the effectiveness of the vaccine during pregnancy in terms of improving maternal, neonatal, and infant health outcomes.[117]

The first Hib vaccine was an unconjugated polysaccharide vaccine composed of the purified PRP capsular polysaccharide. This vaccine induced an ambiguous immune response, did not provide complete protection in children, and provided no antibody protection in infants. This led to the development of the conjugate vaccines in which PRP is covalently linked to a protein.

Currently, 3 licensed vaccines are available. They differ in the protein carrier used, the molecular size of the saccharide, and the method of conjugating the protein to the saccharide. These include HibTITER (HbOC [mutant diphtheria toxin as the carrier protein]), PedvaxHIB (PRP-OMP [major outer membrane protein of N meningitidis serogroup B as the carrier protein]), and ActHIB/OmniHIB (PRP-T [tetanus toxoid as the carrier protein]).[118]

PRP-OMP induces a good immune response after a single dose in infants, but antibody levels after 3 doses are lower than those induced by HbOC and PRP-T. The PRP-OMP vaccine is therefore recommended in American Indians and Alaska native children because of a rapid seroconversion of protective antibodies with the PRP-OMP vaccine. The vaccines are well tolerated, with occasional redness and swelling at the site of vaccination (10-15% of infants), more commonly after the initial dose than after subsequent injections. The estimated effectiveness of the vaccine in children younger than 5 years is 98%.

The combination of Hib conjugate vaccine (PRP-OMP) with hepatitis B vaccine (Recombivax HB) is licensed for use at age 2 months, 4 months, and 12-15 months. The DTaP-Hib is another combination vaccine that is licensed for use but only as a fourth dose in the DTaP and Hib series.[118]

Administer routine immunization of the Hib conjugate vaccine in all infants and children.

In the primary series, administer a 3-dose regimen of HbOC or PRP-T or a 2-dose regimen of PRP-OMP at 2-months intervals, beginning at age 2 months. Any conjugate Hib vaccine can serve as the booster immunization given in children aged 12-15 months. Lack of the booster dose in the United Kingdom might be a reason for the recent increase in Hib disease since the Hib vaccine was introduced there in 1992.

A 2017 stochastic modelling of Hib transmission dynamics aimed to compare the long-term effects of booster vaccination and various booster timings after receipt of the primary series and the subsequent incidence of disease and asymptomatic carriage. The results showed that the incidence of asymptomatic carriage for an average 2-year delay in the booster was comparable or even lower than if the booster was given within 1 year of the primary series. The results were similar for symptomatic disease. The findings highlight the importance of booster vaccination so that the incidence of Hib infections will continue to decrease.[119]

Children with decreased or absent splenic function who have received their full immunization series need not be immunized further.

Children who have received the primary series and a booster dose and are undergoing scheduled splenectomy (eg, for Hodgkin disease, spherocytosis) may benefit from an additional dose of any licensed conjugate vaccine given 7-10 days before the procedure.

Unimmunized children older than 59 months with an underlying disease may be immunized with 2 doses of vaccine 2 months apart.

In 2017, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization released updated vaccination recommendations for adults aged 19 years and older. Recommendations related to the Hib vaccine remained the same as in 2014. Hib vaccination is recommended in the following populations:

• Certain adults at increased risk for Hib infection (patients with anatomical or functional asplenia or sickle cell diseases or who are undergoing elective splenectomy should receive one dose of Hib vaccine) who have not previously received the vaccine, except individuals with human immunodeficiency (HIV) infection or individuals with a low risk for Hib infection
• Adults who have undergone successful hematopoietic stem cell transplantation (HSCT): In these patients, administer a 3-dose series of Hib vaccine 6-12 months posttransplantation, regardless of Hib vaccination status. The vaccine should be given at least 14 days prior to splenectomy. ^{[120, 121, 122]}

The latest recommendations from CDC’s Advisory Committee on Immunization Practices (ACIP) as of 2021 are shown below[123, 124] :

• Routine administration of a conjugate Hib vaccine series beginning at age 2 months

  • Infants 2 through 6 months of age should receive either:
    • A 3-dose series of ActHIB®, Hiberix®, Pentacel®, or Vaxelis™
    • A 2-dose series of PedvaxHIB®
    • Vaccines are interchangeable and should follow a 3-dose schedule if more than 1 brand is used.
    The first dose can be administered as early as 6 weeks old.
• Booster dose of any licensed conjugate Hib vaccine at age 12 through 15 months.

  • The booster dose is administered at least 8 weeks after the most recent Hib vaccination.
  • The booster dose will be dose 3 or 4 depending on vaccine type used in the primary series.
• Below is the catch-up guidance for Hib vaccination for children 4 months through 6 years old:

  • Minimum age for dose 1: 6 weeks
  • Minimum interval between dose 1 and 2: No further doses needed if first dose was administered at age 15 months or older; 4 weeks if first dose was administered before the 1st birthday; 8 weeks (as final dose) if first dose was administered at age 12 through 14 months.
  • Minimum interval between dose 2 and 3: No further doses needed if previous dose was administered at age 15 months or older; 4 weeks if current age is younger than 12 months and first dose was administered at younger than age 7 months and at least 1 previous dose was PRP-T (ActHib®, Pentacel®, Hiberix®), Vaxelis® or unknown; 8 weeks and age 12 through 59 months (as final dose) if current age is younger than 12 months and  first dose was administered at age 7 through 11 months; OR  if current age is 12 through 59 months and  first dose was administered before the 1st birthday and  second dose was administered at younger than 15 months; OR if both doses were PedvaxHIB® and were administered before the 1st birthday
  • Minimum interval between dose 3 and 4: 8 weeks (as final dose). This dose only is necessary for children age 12 through 59 months who received 3 doses before the 1st birthday.
• Contraindications and Precautions

  • Hib vaccines should not be administered to:
    • A person who has ever had a severe allergic reaction (eg, anaphylaxis) after a previous dose
    • A person who has a severe allergy to any vaccine component
    • A person younger than 6 weeks
  • Hib vaccines may be administered, if physician and the parent or patient deem that the benefits of vaccination outweigh the risks, to a person who has a moderate or severe acute illness with or without fever

The currently available NTHi vaccine is PHiD CV10, marketed as Synflorix in Canada and Europe. An efficacy trial showed a protective efficacy of 52.6% against otitis media caused by the pneumococcal serotypes in the vaccine and a protective efficacy of only 35.3% against NTHi otitis.[125, 126] In children younger than 2 years, PHiD-CV10 vaccine effectiveness was 12% against all respiratory tract infections (RTI), 23%  against RTI with acute otitis media, and 10% against RTIs without otitis media.[127]

A phase 1, randomized, observer-blind, placebo-controlled study published in 2016 showed that NTHi vaccine formulations for adults, especially adjuvanted formulations, produced robust antibody responses in terms of humoral and cellular immune responses without any safety issues.[128]

In 2017, a systematic review of 6 placebo-controlled randomized controlled trials studied the effect of oral NTHi vaccination in preventing acute exacerbations of chronic bronchitis and COPD. The study showed a small, non–statistically significant reduction in the incidence of acute exacerbations. However, the study showed a statistically significant increase (80%) of antibiotic use in the placebo group. There was no statistically significant difference regarding hospital admission rates.[129]

The PHiD-CV was subjected to a phase 3, multicenter, open-label, controlled study involving children aged 2-7 years with asplenia and those with splenic dysfunction and was shown to be immunogenic (in terms of antibody geometric mean concentrations and opsonophagocytic activity and geometric mean titers) and well-tolerated.[130]

An investigational vaccine for NTHi and Moraxella catarrhalis is under development and is intended for use in patients with COPD who frequently suffer exacerbations related to these organisms.[131] The phase 1 study of the vaccine administered in a 2-dose schedule showed an acceptable safety, reactogenicity, and immunogenicity profile.

 

Unvaccinated or undervaccinated children younger than 4 years who have household contact with an index patient have a 600-fold increased risk for Hib disease.

Begin chemoprophylaxis as soon as possible because the risk for secondary disease is greatest within a few days after disease onset in the index case. Rifampin is the drug of choice for chemoprophylaxis because it achieves high bactericidal concentrations intracellularly and in mucosal secretions, thereby eradicating 95% of Hib from the nasopharynx. Administer rifampin to all household contacts, including adults, children, and the index patient, if a close household contact is immunocompromised, regardless of immunization status; younger than 48 months and is not completely immunized or unimmunized; or younger than 12 months and has not received the 2- to 3-dose primary series. Chemoprophylaxis is not needed in contacts of patients with non-Hib invasive disease.[118]

Full immunization is defined as having received at least 1 of the following[118] :

• One dose of a Hib conjugate vaccine at age 15 months or older
• Two doses at age 12-14 months
• Two or more doses at age 12 months or older
• Three doses before age 12 months, with a booster dose at age 12 months or older

The CDC states that the recommended primary series in infants should be administered at ages 2, 4, and 6 months or ages 2 and 4 months, depending on the vaccine type used, with a booster dose at age 12-15 months.[16]

If the close contact group includes a fully vaccinated child who is immunocompromised, then make an exception because the vaccination may have been ineffective. A close contact group is defined as persons who reside with the patient or a nonresident who has spent 4 hours or more with the index patient for at least 7 days preceding the day of hospitalization of the patient based on the revised guidelines.[118, 132] Administer rifampin within 7 days after hospitalization of the index patient to ensure effectiveness. The need for chemoprophylaxis has decreased dramatically because the Hib conjugate vaccine now protects many children.

The need for all daycare center contacts to be treated is debatable when a single case has occurred because of uncertainty about the actual risk of secondary Hib disease in this setting.[118]

If 2 or more cases of Hib disease have occurred in a childcare center within 120 days, the consensus is to institute prophylaxis to all attendees and staff members based on the revised guidelines.[132]

Pharyngeal cultures do not need to be obtained to determine prophylaxis, as this delays administration of rifampin.

Administer H influenzae conjugate vaccine to patients younger than 24 months with invasive Hib disease during convalescence regardless of prior immunization. Patients aged 24 months or older with invasive Hib disease do not need immunization.

Patients with recurrent invasive Hib disease despite receiving Hib immunization should undergo immunologic evaluation.

Index patients younger than 2 years who will be in contact with unvaccinated or incompletely immunized children younger than 4 years and who were treated with a regimen other than cefotaxime of ceftriaxone should be treated with rifampin before or at discharge from the hospital because other antibiotics used for the treatment of H influenzae type b (Hib) meningitis do not reliably eradicate Hib from the nasopharynx. Treatment with cefotaxime and ceftriaxone eradicates Hib colonization and therefore eliminates the need for chemoprophylaxis of the index patient.

Search for secondary foci of infection, such as septic arthritis, if patients have prolonged fever during treatment of meningitis.

Droplet precautions should be followed for the first 24 hours following the initiation of appropriate therapy in patients with invasive Hib disease.[118]

If the patient has significantly improved clinically, oral antibiotics may follow parenteral antibiotics started in the hospital to finish the course of treatment.

Adjust antibiotics based on susceptibilities of the involved organism.

Initially, patients with invasive and serious H influenzae infections are best treated with an intravenous third-generation cephalosporin until antibiotic sensitivities become available. It is important to monitor the resistance rates (in the hospital or the region) of H influenzae to the different antibiotics to guide empiric antimicrobial choices while awaiting susceptibility results.

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting. Penicillins are useful in management of mucosal infections caused by nonencapsulated H influenzae. However, up to 25-50% of isolates produce beta-lactamase so are resistant to this class of drugs. Third-generation cephalosporins are highly effective in H influenzae infections. Meropenem or ampicillin and chloramphenicol are alternative regimens.

Azithromycin (Zithromax)

Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.

Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Treats mild-to-moderate microbial infections.

Plasma concentrations are very low, but tissue concentrations are much higher, giving it value in treating intracellular organisms. Has a long tissue half-life.

Cefotaxime (Claforan)

Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms.

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms; arrests bacterial growth by binding to one or more penicillin-binding proteins. Exerts antimicrobial effect by interfering with synthesis of peptidoglycan, a major structural component of bacterial cell wall. Bacteria eventually lyse because of the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested. Highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of dose excreted unchanged in urine, and remainder secreted in bile and, ultimately, in feces as microbiologically inactive compounds. Reversibly binds to human plasma proteins, and binding has been reported to decrease from 95% bound at plasma concentrations < 25 mcg/mL to 85% bound at 300 mcg/mL.

Cefuroxime (Ceftin, Zinacef)

This second-generation cephalosporin maintains gram-positive activity of first-generation cephalosporins; adds activity against Proteus mirabilis, H influenzae, Escherichia coli, Klebsiella pneumoniae, and Moraxella catarrhalis. Binds to penicillin-binding proteins and inhibits final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death. It is not recommended for treatment of Hib meningitis but may be used for other Hib infections. Condition of patient, severity of infection, and susceptibility of microorganism determine proper dose and route of administration.

Ampicillin (Marcillin, Omnipen, Polycillin, Principen)

Broad-spectrum penicillin. Interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take PO medication.

Amoxicillin (Trimox, Amoxil, Trimox)

Derivative of ampicillin and has similar antibacterial spectrum, namely certain gram-positive and gram-negative organisms. Superior bioavailability and stability to gastric acid and has broader spectrum of activity than penicillin. Somewhat less active than that of penicillin against pneumococcus. Penicillin-resistant strains also resistant to amoxicillin, but higher doses may be effective. More effective against gram-negative organisms (eg, Neisseria meningitidis, H influenzae) than penicillin. Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Amoxicillin and clavulanic acid (Augmentin)

Amoxicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. Addition of clavulanate inhibits beta-lactamase–producing bacteria. Good alternative antibiotic for patients allergic or intolerant to the macrolide class. Is usually well tolerated and provides good coverage to most infectious agents. Not effective against Mycoplasma and Legionella species. The half-life of oral dosage form is 1-1.3 h. Has good tissue penetration but does not enter CSF. For children >3 months, base dosing protocol on amoxicillin content. Because of different amoxicillin/clavulanic acid ratios in 250-mg tab (250/125) vs 250-mg chewable tab (250/62.5), do not use 250-mg tab until child weighs >40 kg. The bid dosing schedule reduces incidence of diarrhea.

Chloramphenicol (Chloromycetin)

May be used in patients who are allergic to penicillins and cephalosporins. Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Active in vitro against a wide variety of bacteria, including gram-positive, gram-negative, aerobic, and anaerobic organisms. Well-absorbed from GI tract and metabolized in the liver, where it is inactivated by conjugation with glucuronic acid and then excreted by the kidneys. Oral form is not available in the United States.

Erythromycin and sulfisoxazole (Eryzole, Pediazole)

Erythromycin is a macrolide antibiotic with a large spectrum of activity. Erythromycin binds to the 50S ribosomal subunit of the bacteria, which inhibits protein synthesis. Sulfisoxazole expands erythromycin's coverage to include gram-negative bacteria. Sulfisoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid. Good choice for PO therapy for otitis media. May be used in patients who are allergic to penicillins and cephalosporins.

Meropenem (Merrem IV)

Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. Effective against most gram-positive and gram-negative bacteria. Has slightly increased activity against gram-negative species and slightly decreased activity against staphylococci and streptococci compared with imipenem. In contrast to imipenem, indicated for treatment of bacterial meningitis, including pediatric meningitis.

Rifampin (Rifadin)

Used for chemoprophylaxis in Hib infections.

Class Summary

These agents are used as adjunctive therapy in H influenza meningitis for the anti-inflammatory effects and prevention of sensorineural deafness. Administer before or with antibiotics, not after. Utility of steroids has been demonstrated primarily in nonimmunized children, and its usefulness in adults or vaccinated children is not known.

Dexamethasone (Decadron, Baldex)

Has many pharmacologic benefits but significant adverse effects. Stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). The inhibition of chemotactic factors and factors that increase capillary permeability inhibits recruitment of inflammatory cells into affected areas. Suppresses lymphocyte proliferation through direct cytolysis and inhibits mitosis. Breaks down granulocyte aggregates and improves pulmonary microcirculation.

Adverse effects are hyperglycemia, hypertension, weight loss, GI bleeding or perforation synthesis, cerebral palsy, adrenal suppression, and death. Most of the adverse effects of corticosteroids are dose-dependent or duration-dependent.

Readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Lacks salt-retaining property of hydrocortisone.

Patients can be switched from an IV to PO regimen in a 1:1 ratio.