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Sections Haemophilus Influenzae Infections
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Treatment
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References

Treatment

Medical Care

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]

Surgical Care

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.

Consultations

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.

Prevention

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.

Further Outpatient Care

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.

Further Inpatient Care

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]

Inpatient & Outpatient Medications

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.

Medication

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