Haemophilus influenzae: Infectious substances pathogen safety data sheet

Section I – Infectious agent

Name

Haemophilus influenzae

Agent type

Bacteria

Taxonomy

Family

Pasteurellaceae

Genus

Haemophilus

Species

Influenzae

Synonym or cross-reference

Pfeiffer’s bacillus, Bacterium influenzae, Coccobacillus pfeifferi, and Haemophilus meningitis^{Footnote 1}^{Footnote 2}.

Characteristics

Brief description

H. influenzaeis a Gram-negative, coccobacillus or rod-shaped bacterium measuring 0.3-0.5 μm by 0.5-3.0 μm^{Footnote 3}. Its genome is approximately 1.9 Mb^{Footnote 3}^{Footnote 4}. H. influenzae are non-motile, facultative anaerobes that require factor X (hemin) and factor V (NAD) to grow^{Footnote 3}. There are 8 biovars (I-VIII), defined based on indole, urease, and ornithine decarboxylase activity^{Footnote 5}. Some strains produce a polysaccharide capsule and can be further classified into one of six serovars (a to f). Strains without capsules are referred to as non-typeable H. influenzae (NTHi).

Properties

H. influenzae is a commensal bacterium, but several biogroups, including H. influenzae biogroup aegyptius, can also cause disease in humans^{Footnote 3}. Both encapsulated and NTHi strains can cause invasive disease at normally sterile sites where H. influenzaeis not isolated from healthy individuals^{Footnote 6}^{Footnote 7}.H. influenzae can enter the bloodstream and disseminate to other sites of the body^{Footnote 8}. H. influenzae serotype b (Hib) is the most virulent^{Footnote 9}.

Section II – Hazard identification

Pathogenicity and toxicity

H. influenzae is a common commensal bacterium of the upper respiratory tract, but it can also cause localized (e.g., infections of the upper and lower respiratory tract, paranasal sinuses, middle ears, conjunctivae, skin) or invasive disease (e.g., meningitis, septicemia, epiglottitis, pneumonia, pericarditis, septic arthritis)^{Footnote 3}^{Footnote 6}^{Footnote 7}.

H. influenzae-associated meningitis affects young children more frequently than adults^{Footnote 10}. Symptoms include headache, fever, nausea, vomiting, neck stiffness, and altered mental status^{Footnote 11}. The case-fatality rate is approximately 4%, even with treatment^{Footnote 10}. Neurologic sequelae, including hearing loss and learning/behavioural deficiencies, affect up to 25% of survivors^{Footnote 12}^{Footnote 13}^{Footnote 14} . Hib is more commonly associated with meningitis in children, whereas NTHi is more commonly associated with meningitis in adults^{Footnote 10}. Non-type b capsulated H. influenzae also cause meningitis^{Footnote 10}^{Footnote 15}.

Acute epiglottitis infection is associated with capsulated H. influenzae , and is characterized by inflammation of the epiglottis^{Footnote 10}^{Footnote 15}^{Footnote 16}. Symptoms include fever, difficulty breathing, sore throat, and drooling and can progress rapidly to fatal airway obstruction in some cases^{Footnote 16}^{Footnote 17}. The case-fatality rate is approximately 3%^{Footnote 10}.

H. influenzae-associated cellulitis affects children and adults^{Footnote 10}. Signs and symptoms include fever, malaise, tenderness and discolouration of the skin (usually the face or neck)^{Footnote 18}^{Footnote 19} . The case-fatality rate is less than 2%^{Footnote 10}.

Acute otitis media primarily affects children and is characterized by inflammation and accumulation of fluid in the middle ear^{Footnote 8}^{Footnote 20}. Signs and symptoms include fever, ear pain, and in some cases discharge from the ear^{Footnote 8}^{Footnote 20}. NTHi causes 25-35% of acute otitis media cases^{Footnote 21}. Approximately 10% of children are prone to recurrent otitis media infections^{Footnote 8}.

NTHi, Hib, and non-type b capsulated H. influenzae-associated pneumonia affects children and adults^{Footnote 10}^{Footnote 22}. Symptoms include fever, cough, and purulent sputum^{Footnote 23}. NTHi is highly associated with pneumonia in adults over 65 years of age^{Footnote 10}. The case-fatality rate is 5% and 15% for Hib and NTHi-associated pneumonia, respectively^{Footnote 10}. In adults, H. influenzae is also associated with acute exacerbations of chronic obstructive pulmonary disease^{Footnote 24}.

H. influenzae is occasionally associated with osteomyelitis^{Footnote 8}, infective endocarditis^{Footnote 25}, and urethritis^{Footnote 26}. Invasive NTHi infection has been associated with early pregnancy loss^{Footnote 27}.

Epidemiology

Up to 70% of healthy children harbour H. influenzae in their nasopharynx; NTHi strains being the most commonly isolated^{Footnote 3}^{Footnote 28}. Adults have a carriage rate of 1 to 7%^{Footnote 3}^{Footnote 29}. Prior to 1980, Hib was a common cause of invasive disease (e.g., meningitis, pneumonia, epiglottitis, septicaemia, cellulitis) in children globally^{Footnote 30}. Widespread use of pediatric Hib vaccines has reduced global incidence of Hib invasive disease and deaths by 90% between 2000 and 2015^{Footnote 31}. In 2015, estimated Hib-associated global cases and deaths in children were 975,000 and 29,800, respectively^{Footnote 31}. Incidence of Hib-associated disease in children in the Western Pacific, Southeast Asia, and Africa are estimated to be 317,238 and 75 cases per 100,000 population, respectively^{Footnote 31}.

As a result of Hib vaccination, NTHi (72-78%) and non-type b serotypes are responsible for an increasing proportion of invasive H. influenzae diseases in developed countries^{Footnote 6}^{Footnote 32}^{Footnote 33} . Incidence of invasive H. influenzae disease in Europe, the United States, and Canada is 0.6 - 1.9 cases per 100,000 people, with the highest incidence among adults over 65 years of age (6.3 per 100,000 population) and children less than 1 year old (8.45 per 100,000 population)^{Footnote 6}^{Footnote 32}^{Footnote 34}. Outbreaks of non-Hib serotype and NTHi-associated disease in care facilities have been reported^{Footnote 35}^{Footnote 36} .

An estimated five million acute otitis media cases occur annually in children in the United States^{Footnote 37}. Approximately one third of acute otitis media cases are caused by NTHi^{Footnote 21}.

Individuals with human immunodeficiency virus (HIV)^{Footnote 38}, immunoglobulin deficiencies^{Footnote 39}^{Footnote 40} , cystic fibrosis^{Footnote 41}, splenectomy^{Footnote 42}, and sickle cell disease^{Footnote 43}^{Footnote 44}^{Footnote 45} are more susceptible to invasive H. influenzae infection. Individuals with skull trauma or cerebrospinal fluid (CSF) leaks are at greater risk for H. influenzae meningitis^{Footnote 46}^{Footnote 47} . Adults over 65 years of age and children less than 1 year old are more susceptible to H. influenzae infection^{Footnote 6}^{Footnote 32}.

Host range

Natural host(s)

Humans are the only natural host of H. influenzae^{Footnote 3}.

Other host(s)

Rodents (e.g., chinchillas) have been experimentally infected^{Footnote 48}.

Infectious dose

Unknown.

Incubation period

Incubation period is unknown but is probably between 2-4 days for Hib^{Footnote 49}.

Communicability

H. influenzae is transmitted among individuals with close contact, such as members of the same household or in daycare settings^{Footnote 50}^{Footnote 51}^{Footnote 52}^{Footnote 53} , via inhalation of respiratory droplets or direct contact with respiratory secretions^{Footnote 54}. Disease is not communicable 48 hours after initiation of effective antibiotic treatment^{Footnote 55}.

Section III – Dissemination

Reservoir

Humans.

Zoonosis

None.

Vectors

None.

Section IV – Stability and viability

Drug susceptibility/resistance

H. influenzae is susceptible to cephalosporins (e.g., cefotaxime^{Footnote 56}, ceftazidime^{Footnote 56}, cefepime^{Footnote 57}, ceftobiprole^{Footnote 58}, cefditoren^{Footnote 59}, ceftaroline^{Footnote 60}^{Footnote 61}); carbapenems (e.g., meropenem^{Footnote 56}); chloramphenicol^{Footnote 57}; quinolones (e.g., ciprofloxacin^{Footnote 56}, delafloxacin^{Footnote 62}, moxifloxacin^{Footnote 62}, levonadifloxacin^{Footnote 63}); omadacycline^{Footnote 64}; tigecycline^{Footnote 65}^{Footnote 66} ; eravacycline^{Footnote 67}; hexylresorcinol^{Footnote 68}; and Lefamulin^{Footnote 69}.

H. influenzae antimicrobial resistance profiles vary geographically^{Footnote 70}. H. influenzae is generally not susceptible to macrolides^{Footnote 57}. H. influenzae resistance to β-lactam (e.g., ampicillin, amoxicillin) antibiotics is prevalent globally, ranging from 17% to 31% in North America and up to 60% in some parts of Asia^{Footnote 57}^{Footnote 61}^{Footnote 70}^{Footnote 71}^{Footnote 72}^{Footnote 73}^. Some β-lactam-resistant H. influenzae strains produce β-lactamase; others are β-lactamase-negative ampicillin-resistant^{Footnote 57}^{Footnote 71}^{Footnote 74}. Resistance of some β-lactamase-producing strains can be overcome by treatments that use a β-lactam antibiotic in combination with a β-lactamase inhibitor (e.g., amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam)^{Footnote 5}.

Trimethoprim/sulfamethoxazole-resistance is prevalent in all regions, ranging from 14% to 30% in North America and 70% in parts of Asia^{Footnote 57}^{Footnote 70}^{Footnote 72}. Quinolone-resistant H. influenzae strains have been described^{Footnote 4}^{Footnote 71}^{Footnote 73}. Chloramphenicol or cephalosporin (e.g., cefaclor) resistance is observed occasionally^{Footnote 57}^{Footnote 70}^{Footnote 73}^{Footnote 75}.

Multidrug resistant H. influenzae strains (ampicillin, chloramphenicol, trimethoprim/sulfamethoxazole) and extensively drug resistant strains (ampicillin, amoxicillin/clavulanate, cefuroxime, levofloxacin, trimethoprim/sulfamethoxazole) have been described in parts of Asia^{Footnote 71}^{Footnote 73}^{Footnote 76}.

Susceptibility to disinfectants

Chloramine-T, sodium hypochlorite, povidone-iodine, glutaraldehyde (2%), chlorhexidine, peracetic acid (0.35%), and ethanol (70%) are effective against Haemophilus species^{Footnote 77}^{Footnote 78}.

Physical inactivation

UV irradiation^{Footnote 79}^{Footnote 80} , dry heat treatment (170°C for 1 hour) and moist heat treatment (121°C for 15 minutes) are effective at inactivating Haemophilus species^{Footnote 81}.

Survival outside host

Hib in nasal secretions persists on surfaces (e.g., wood, textiles) for approximately 12 hours^{Footnote 82}^{Footnote 83} .

Section V – First aid/medical

Surveillance

Monitor for symptoms. Diagnosis is usually confirmed by culture and/or PCR^{Footnote 5}^{Footnote 84}^{Footnote 85} . Commercial biochemical identification systems can also be used to identify H. influenzae^{Footnote 5}^{Footnote 86}.

Note: The specific recommendations for surveillance in the laboratory should come from the medical surveillance program, which is based on a local risk assessment of the pathogens and activities being undertaken, as well as an overarching risk assessment of the biosafety program as a whole. More information on medical surveillance is available in the Canadian Biosafety Handbook (CBH).

First aid/treatment

H. influenzae infections can be treated with appropriate antibiotics^{Footnote 54}. If airways are blocked, more invasive procedures may be necessary.

Note: The specific recommendations for first aid/treatment in the laboratory should come from the post-exposure response plan, which is developed as part of the medical surveillance program. More information on the post-exposure response plan can be found in the CBH .

Immunization

Polyribosylribitol phosphate (PRP) vaccines for Hib disease are used in most countries to immunize infants and toddlers^{Footnote 31}. Vaccine formulations for NTHi are currently in phase 2 clinical trials for adults with chronic obstructive pulmonary disease^{Footnote 24}^{Footnote 87}. Inclusion of H. influenzae-derived protein D in pneumococcal conjugate vaccines resulted in up to 35% reduction of NTHi-associated acute otitis media^{Footnote 88}^{Footnote 89} . A more efficacious vaccine for NTHi-induced otitis media in children is an active area of research^{Footnote 48}^{Footnote 90}.

Note: More information on the medical surveillance program can be found in the CBH, and by consulting the Canadian Immunization Guide.

Prophylaxis

Rifampin may be recommended for non-immunized or immunocompromised direct contacts of individuals with Hib disease^{Footnote 54}.

Note: More information on prophylaxis as part of the medical surveillance program can be found in the CBH .

Section VI – Laboratory hazard

Laboratory-acquired infections

Five H. influenzae-associated laboratory acquired infections were reported prior to 1982^{Footnote 91}^{Footnote 92} . One technician developed H. influenzae-associated conjunctivitis after infectious material splashed into his eye^{Footnote 91}.

Note: Please consult the Canadian Biosafety Standard (CBS) and CBH for additional details on requirements for reporting exposure incidents. A Canadian biosafety guideline describing notification and reporting procedures is also available.

Sources/specimens

Blood, cerebrospinal fluid, sputum, middle ear fluid, urine.

Primary hazards

Autoinoculation with infectious material and exposure of mucous membranes/skin to infectious material.

Special hazards

None.

Section VII – Exposure controls/personal protection

Risk group classification

H. influenzae is a Risk Group (RG) 2 human pathogen and RG1 animal pathogen^{Footnote 93}^{Footnote 94}. H. influenzae subsp. murium is a RG1 human pathogen and RG2 animal pathogen^{Footnote 93}.

Containment requirements

Containment Level 2 facilities, equipment, and operational practices outlined in the CBS for work involving infectious or potentially infectious materials, animals, or cultures.

Protective clothing

The applicable Containment Level 2 requirements for personal protective equipment and clothing outlined in the CBS are to be followed. The personal protective equipment could include the use of a lab coat and dedicated footwear (e.g., boots, shoes) or additional protective footwear (e.g., boot or shoe covers) where floors may be contaminated (e.g., animal cubicles, PM rooms), gloves when direct skin contact with infected materials or animals is unavoidable, and eye protection where there is a known or potential risk of exposure to splashes.

Note: A local risk assessment will identify the appropriate hand, foot, head, body, eye/face, and respiratory protection, and the personal protective equipment requirements for the containment zone and work activities must be documented.

Other precautions

A biological safety cabinet (BSC) or other primary containment devices to be used for activities with open vessels, based on the risks associated with the inherent characteristics of the regulated material, the potential to produce infectious aerosols or aerosolized toxins, the handling of high concentrations of regulated materials, or the handling of large volumes of regulated materials.

Use of needles and syringes to be strictly limited. Bending, shearing, re-capping, or removing needles from syringes to be avoided, and if necessary, performed only as specified in standard operating procedures (SOPs). Additional precautions are required with work involving animals or large-scale activities.

Additional information

For diagnostic laboratories handling primary specimens that may contain H. influenzae, the following resources may be consulted:

Section VIII – Handling and storage

Spills

Allow aerosols to settle. Wearing personal protective equipment, gently cover the spill with absorbent paper towel and apply suitable disinfectant, starting at the perimeter and working towards the centre. Allow sufficient contact time before clean up (CBH).

Disposal

All materials/substances that have come in contact with the regulated materials should be completely decontaminated before they are removed from the containment zone or standard operating procedures (SOPs) to be in place to safely and securely move or transport waste out of the containment zone to a designated decontamination area / third party. This can be achieved by using decontamination technologies and processes that have been demonstrated to be effective against the regulated material, such as chemical disinfectants, autoclaving, irradiation, incineration, an effluent treatment system, or gaseous decontamination (CBH).

Storage

Containment Level 2: The applicable Containment Level 2 requirements for storage outlined in the CBS are to be followed. Primary containers of regulated materials removed from the containment zone to be labelled, leakproof, impact resistant, and kept either in locked storage equipment or within an area with limited access.

Section IX – Regulatory and other information

Canadian regulatory information

Controlled activities with H. influenzae require a Human Pathogens and Toxins licence, issued by the Public Health Agency of Canada^{Footnote 94}. Invasive H. influenzae disease is a nationally notifiable disease in Canada.

The following is a non-exhaustive list of applicable designations, regulation, or legislation:

Last file update

2020

Prepared by

Centre for Biosecurity, Public Health Agency of Canada.

Disclaimer

The scientific information, opinions, and recommendations contained in this Pathogen Safety Data Sheet have been developed based on or compiled from trusted sources available at the time of publication. Newly discovered hazards are frequent and this information may not be completely up to date. The Government of Canada accepts no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information.

Persons in Canada are responsible for complying with the relevant laws, including regulations, guidelines and standards applicable to the import, transport, and use of pathogens in Canada set by relevant regulatory authorities, including the Public Health Agency of Canada, Health Canada, Canadian Food Inspection Agency, Environment and Climate Change Canada, and Transport Canada. The risk classification and related regulatory requirements referenced in this Pathogen Safety Data Sheet, such as those found in the Canadian Biosafety Standard, may be incomplete and are specific to the Canadian context. Other jurisdictions will have their own requirements.

References

Footnote 1

National Center for Biotechnology Information. Taxonomy Browser. NCBI:txid727. Haemophilus Influenzae. 2020:.

Return to footnote 1 referrer

Footnote 2

Lindsay, J. W., E. C. Rice, and M. A. Selinger. 1940. The treatment of meningitis due to Hemophilus influenzae (Pfeiffer's bacillus): A review of 108 cases. J. Pediatr. 17:220-227.

Return to footnote 2 referrer

Footnote 3

Kilian, M. 2005. Genus III. Haemophilus, p. 883. G. Garrity, D. J. Brenner, N. R. Krieg, and J. T. Staley (eds.), Bergey's Manual of Systematic Bacteriology, Second Edition. Volume Two: The Proteobacteria. Part B: The Gammaproteobacteria. Springer.

Return to footnote 3 referrer

Footnote 4

Tanaka, E., T. Wajima, H. Nakaminami, and N. Noguchi. 2020. Whole-genome sequence of Haemophilus influenzae ST422 outbreak clone strain 2018-Y40 with low quinolone susceptibility isolated from a paediatric patient. J. Glob. Antimicrob. Resist.

Return to footnote 4 referrer

Footnote 5

Ledeboer, N. A., and G. V. Doern. 2015. Haemophilus, p. 667. J. H. Jorgensen and M. A. Pfaller (eds.), Manual of Clinical Microbiology. ASM Press.

Return to footnote 5 referrer

Footnote 6

Whittaker, R., A. Economopoulou, J. G. Dias, E. Bancroft, M. Ramliden, L. P. Celentano, and European Centre for Disease Prevention and Control Country Experts for Invasive Haemophilus influenzae Disease. 2017. Epidemiology of Invasive Haemophilus influenzae Disease, Europe, 2007-2014. Emerg. Infect. Dis. 23:396-404.

Return to footnote 6 referrer

Footnote 7

Government of Canada. 2009. Case Definitions for Communicable Diseases under National Surveillance - 2009. Haemophilus influenzae non-b, Invasive Disease. 2020:.

Return to footnote 7 referrer

Footnote 8

Agrawal, A., and T. F. Murphy. 2011. Haemophilus influenzae infections in the H. influenzae type b conjugate vaccine era. J. Clin. Microbiol. 49:3728-3732.

Return to footnote 8 referrer

Footnote 9

Zwahlen, A., J. S. Kroll, L. G. Rubin, and E. R. Moxon. 1989. The molecular basis of pathogenicity in Haemophilus influenzae: comparative virulence of genetically-related capsular transformants and correlation with changes at the capsulation locus cap. Microb. Pathog. 7:225-235.

Return to footnote 9 referrer

Footnote 10

Ladhani, S., M. P. Slack, P. T. Heath, A. von Gottberg, M. Chandra, M. E. Ramsay, and European Union Invasive Bacterial Infection Surveillance participants. 2010. Invasive Haemophilus influenzae Disease, Europe, 1996-2006. Emerg. Infect. Dis. 16:455-463.

Return to footnote 10 referrer

Footnote 11

Fuentes-Antrás, J., M. Ramírez-Torres, E. Osorio-Martínez, M. Lorente, A. Lorenzo-Almorós, O. Lorenzo, and M. Górgolas. 2019. Acute Community-Acquired Bacterial Meningitis: Update on Clinical Presentation and Prognostic factors. New Microbiol. 41:81-87.

Return to footnote 11 referrer

Footnote 12

Taylor, H. G., E. L. Mills, A. Ciampi, R. du Berger, G. V. Watters, R. Gold, N. MacDonald, and R. H. Michaels. 1990. The sequelae of Haemophilus influenzae meningitis in school-age children. N. Engl. J. Med. 323:1657-1663.

Return to footnote 12 referrer

Footnote 13

Wenger, J. D. 1998. Epidemiology of Haemophilus influenzae type b disease and impact of Haemophilus influenzae type b conjugate vaccines in the United States and Canada. Pediatr. Infect. Dis. J. 17:S132-6.

Return to footnote 13 referrer

Footnote 14

Smith, A. L. 1987. Pathogenesis of Haemophilus influenzae meningitis. Pediatr. Infect. Dis. J. 6:783-786.

Return to footnote 14 referrer

Footnote 15

Soeters, H. M., S. E. Oliver, I. D. Plumb, A. E. Blain, T. Zulz, B. C. Simons, M. Barnes, M. M. Farley, L. H. Harrison, R. Lynfield, S. Massay, J. McLaughlin, A. G. Muse, S. Petit, W. Schaffner, A. Thomas, S. Torres, J. Watt, T. Pondo, M. J. Whaley, F. Hu, X. Wang, E. C. Briere, and M. G. Bruce. 2020. Epidemiology of Invasive Haemophilus influenzae Serotype a Disease-United States, 2008-2017. Clin. Infect. Dis.

Return to footnote 15 referrer

Footnote 16

Mayo-Smith, M. F., J. W. Spinale, C. J. Donskey, M. Yukawa, R. H. Li, and F. J. Schiffman. 1995. Acute epiglottitis. An 18-year experience in Rhode Island. Chest. 108:1640-1647.

Return to footnote 16 referrer

Footnote 17

Law, B. J., D. Draper, E. L. Mills, M. Allard, C. Nijssen-Jordan, R. Bortolossi, N. E. Macdonald, A. A. Al-Twaim, W. Albritton, G. Kasian, L. Rea, S. Cronk, and R. Morris. 1990. Epiglottitis in Canada: A multiregional review. Can. J. Infect. Dis. 1:15-22.

Return to footnote 17 referrer

Footnote 18

Landwirth, J. 1977. Bilateral cellulitis of cheeks in an infant due to Hemophilus influenzae. Clin. Pediatr. (Phila). 16:182-184.

Return to footnote 18 referrer

Footnote 19

Kroshinsky, D., M. E. Grossman, and L. P. Fox. 2007. Approach to the patient with presumed cellulitis. Semin. Cutan. Med. Surg. 26:168-178.

Return to footnote 19 referrer

Footnote 20

Silva, M. D., and S. Sillankorva. 2019. Otitis media pathogens - A life entrapped in biofilm communities. Crit. Rev. Microbiol. 45:595-612.

Return to footnote 20 referrer

Footnote 21

Murphy, T. F., H. Faden, L. O. Bakaletz, J. M. Kyd, A. Forsgren, J. Campos, M. Virji, and S. I. Pelton. 2009. Nontypeable Haemophilus influenzae as a pathogen in children. Pediatr. Infect. Dis. J. 28:43-48.

Return to footnote 21 referrer

Footnote 22

Slack, M. P. E. 2017. The evidence for non-typeable Haemophilus influenzae as a causative agent of childhood pneumonia. Pneumonia (Nathan). 9:9-017-0033-2. eCollection 2017.

Return to footnote 22 referrer

Footnote 23

Forstner, C., G. Rohde, J. Rupp, H. Schuette, S. R. Ott, S. Hagel, N. Harrison, F. Thalhammer, H. von Baum, N. Suttorp, T. Welte, M. W. Pletz, and CAPNETZ Study Group. 2016. Community-acquired Haemophilus influenzae pneumonia--New insights from the CAPNETZ study. J. Infect. 72:554-563.

Return to footnote 23 referrer

Footnote 24

Wilkinson, T. M. A., E. Aris, S. C. Bourne, S. C. Clarke, M. Peeters, T. G. Pascal, L. Taddei, A. C. Tuck, V. L. Kim, K. K. Ostridge, K. J. Staples, N. P. Williams, A. P. Williams, S. A. Wootton, and J. M. Devaster. 2019. Drivers of year-to-year variation in exacerbation frequency of COPD: analysis of the AERIS cohort. ERJ Open Res. 5:00248-2018.

Return to footnote 24 referrer

Footnote 25

Csukas, S. R., F. Elbl, and G. S. Marshall. 1992. Type b and non-type b Haemophilus influenzae endocarditis. Pediatr. Infect. Dis. J. 11:1053-1056.

Return to footnote 25 referrer

[26] Ito, S., K. Hatazaki, K. Shimuta, H. Kondo, K. Mizutani, M. Yasuda, K. Nakane, T. Tsuchiya, S. Yokoi, M. Nakano, M. Ohinishi, and T. Deguchi. 2017. Haemophilus influenzae Isolated From Men With Acute Urethritis: Its Pathogenic Roles, Responses to Antimicrobial Chemotherapies, and Antimicrobial Susceptibilities. Sex. Transm. Dis. 44:205-210.

Footnote 27

Cevik, M., O. L. Moncayo-Nieto, and M. J. Evans. 2020. Non-typeable Haemophilus influenzae-associated early pregnancy loss: an emerging neonatal and maternal pathogen. Infection. 48:285-288.

Return to footnote 27 referrer

Footnote 28

Ortiz-Romero, M. D. M., M. P. Espejo-García, S. Alfayate-Miguelez, F. J. Ruiz-López, D. Zapata-Hernandez, A. J. Gonzalez-Pacanowska, and Collaborators of Study Group of Infectious Diseases in the Child in Cartagena. 2017. Epidemiology of Nasopharyngeal Carriage by Haemophilus influenzae in Healthy Children: A Study in the Mediterranean Coast Region. Pediatr. Infect. Dis. J. 36:919-923.

Return to footnote 28 referrer

Footnote 29

Drayß, M., H. Claus, K. Hubert, K. Thiel, A. Berger, A. Sing, M. V. Linden, U. Vogel, and T. T. Lâm. 2019. Asymptomatic carriage of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Group A Streptococcus and Staphylococcus aureus among adults aged 65 years and older. PLoS One. 14:e0212052.

Return to footnote 29 referrer

Footnote 30

Peltola, H. 2000. Worldwide Haemophilus influenzae type b disease at the beginning of the 21st century: global analysis of the disease burden 25 years after the use of the polysaccharide vaccine and a decade after the advent of conjugates. Clin. Microbiol. Rev. 13:302-317.

Return to footnote 30 referrer

Footnote 31

Wahl, B., K. L. O'Brien, A. Greenbaum, A. Majumder, L. Liu, Y. Chu, I. Lukšić, H. Nair, D. A. McAllister, H. Campbell, I. Rudan, R. Black, and M. D. Knoll. 2018. Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000-15. Lancet Glob. Health. 6:e744-e757.

Return to footnote 31 referrer

Footnote 32

Soeters, H. M., A. Blain, T. Pondo, B. Doman, M. M. Farley, L. H. Harrison, R. Lynfield, L. Miller, S. Petit, A. Reingold, W. Schaffner, A. Thomas, S. M. Zansky, X. Wang, and E. C. Briere. 2018. Current Epidemiology and Trends in Invasive Haemophilus influenzae Disease-United States, 2009-2015. Clin. Infect. Dis. 67:881-889.

Return to footnote 32 referrer

Footnote 33

Cerqueira, A., S. Byce, R. S. W. Tsang, F. B. Jamieson, J. V. Kus, and M. Ulanova. 2019. Continuing surveillance of invasive Haemophilus influenzae disease in northwestern Ontario emphasizes the importance of serotype a and non-typeable strains as causes of serious disease: a Canadian Immunization Research Network (CIRN) Study. Can. J. Microbiol. 65:805-813.

Return to footnote 33 referrer

Footnote 34

Public Health Agency of Canada. 2017. Notifiable Disease Pre-Built Charts. Disease over time, 1924-2017. 2020:.

Return to footnote 34 referrer

Footnote 35

Van, D. M., C. Walden, E. S. Walker, S. A. Reynolds, F. Levy, and F. A. Sarubbi. 2007. An outbreak of infections caused by non-typeable Haemophilus influenzae in an extended care facility. J. Hosp. Infect. 66:59-64.

Return to footnote 35 referrer

Footnote 36

Miyahara, R., M. Suzuki, K. Morimoto, B. Chang, S. Yoshida, S. Yoshinaga, M. Kitamura, M. Chikamori, K. Oishi, T. Kitamura, and M. Ishida. 2018. Nosocomial Outbreak of Upper Respiratory Tract Infection With β-Lactamase-Negative Ampicillin-Resistant Nontypeable Haemophilus influenzae. Infect. Control Hosp. Epidemiol. 39:652-659.

Return to footnote 36 referrer

Footnote 37

Kaur, R., M. Morris, and M. E. Pichichero. 2017. Epidemiology of Acute Otitis Media in the Postpneumococcal Conjugate Vaccine Era. Pediatrics. 140:e20170181.

Return to footnote 37 referrer

Footnote 38

Steinhart, R., A. L. Reingold, F. Taylor, G. Anderson, and J. D. Wenger. 1992. Invasive Haemophilus influenzae infections in men with HIV infection. JAMA. 268:3350-3352.

Return to footnote 38 referrer

Footnote 39

Fieschi, C., M. Malphettes, L. Galicier, and E. Oksenhendler. 2006. Adult-onset primary hypogammaglobulinemia. Presse Med. 35:887-894.

Return to footnote 39 referrer

Footnote 40

Martinot, M., L. Oswald, E. Parisi, E. Etienne, N. Argy, I. Grawey, D. De Briel, M. M. Zadeh, L. Federici, G. Blaison, C. Koebel, B. Jaulhac, Y. Hansmann, and D. Christmann. 2014. Immunoglobulin deficiency in patients with Streptococcus pneumoniae or Haemophilus influenzae invasive infections. Int. J. Infect. Dis. 19:79-84.

Return to footnote 40 referrer

Footnote 41

Cardines, R., M. Giufrè, A. Pompilio, E. Fiscarelli, G. Ricciotti, G. Di Bonaventura, and M. Cerquetti. 2012. Haemophilus influenzae in children with cystic fibrosis: antimicrobial susceptibility, molecular epidemiology, distribution of adhesins and biofilm formation. Int. J. Med. Microbiol. 302:45-52.

Return to footnote 41 referrer

Footnote 42

Konradsen, H. B., C. Rasmussen, P. Ejstrud, and J. B. Hansen. 1997. Antibody levels against Streptococcus pneumoniae and Haemophilus influenzae type b in a population of splenectomized individuals with varying vaccination status. Epidemiol. Infect. 119:167-174.

Return to footnote 42 referrer

Footnote 43

Battersby, A. J., H. H. Knox-Macaulay, and E. D. Carrol. 2010. Susceptibility to invasive bacterial infections in children with sickle cell disease. Pediatr. Blood Cancer. 55:401-406.

Return to footnote 43 referrer

Footnote 44

Williams, T. N., S. Uyoga, A. Macharia, C. Ndila, C. F. McAuley, D. H. Opi, S. Mwarumba, J. Makani, A. Komba, M. N. Ndiritu, S. K. Sharif, K. Marsh, J. A. Berkley, and J. A. Scott. 2009. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet. 374:1364-1370.

Return to footnote 44 referrer

Footnote 45

Pearson, H. A. 1977. Sickle cell anemia and severe infections due to encapsulated bacteria. J. Infect. Dis. 136 Suppl:S25-30.

Return to footnote 45 referrer

Footnote 46

Spagnuolo, P. J., J. J. Ellner, P. I. Lerner, M. C. McHenry, F. Flatauer, P. Rosenberg, and M. S. Rosenthal. 1982. Haemophilus influenzae meningitis: the spectrum of disease in adults. Medicine (Baltimore). 61:74-85.

Return to footnote 46 referrer

Footnote 47

Tang, L. M., S. T. Chen, and Y. R. Wu. 1998. Haemophilus influenzae meningitis in adults. Diagn. Microbiol. Infect. Dis. 32:27-32.

Return to footnote 47 referrer

Footnote 48

Whitby, P. W., D. J. Morton, H. J. Mussa, L. Mirea, and T. L. Stull. 2020. A bacterial vaccine polypeptide protective against nontypable Haemophilus influenzae. Vaccine. 38:2960-2970.

Return to footnote 48 referrer

Footnote 49

Webber, R. 2005. Communicable disease epidemiology and control: a global perspective (2nd ed.). CABI publishing.

Return to footnote 49 referrer

Footnote 50

Watanabe, H., K. Hoshino, R. Sugita, N. Asoh, K. Watanabe, K. Oishi, and T. Nagatake. 2004. Possible high rate of transmission of nontypeable Haemophilus influenzae, including beta-lactamase-negative ampicillin-resistant strains, between children and their parents. J. Clin. Microbiol. 42:362-365.

Return to footnote 50 referrer

Footnote 51

Goetz, M. B., H. O'Brien, J. M. Musser, and J. I. Ward. 1994. Nosocomial transmission of disease caused by nontypeable strains of Haemophilus influenzae. Am. J. Med. 96:342-347.

Return to footnote 51 referrer

Footnote 52

Loos, B. G., J. M. Bernstein, D. M. Dryja, T. F. Murphy, and D. P. Dickinson. 1989. Determination of the epidemiology and transmission of nontypable Haemophilus influenzae in children with otitis media by comparison of total genomic DNA restriction fingerprints. Infect. Immun. 57:2751-2757.

Return to footnote 52 referrer

Footnote 53

Halsey, N. A., C. Korock, T. L. Johansen, and M. P. Glode. 1980. Intralitter transmission of haemophilus influenzae type b in infant rats and rifampin eradication of nasopharyngeal colonization. J. Infect. Dis. 142:739-743.

Return to footnote 53 referrer

Footnote 54

U. S. Department of Health and Human Services, and Centers for Disease Control and Prevention. 2014. Prevention and Control ofHaemophilus influenzae Type b Disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Vol. 63/No. 1:.

Return to footnote 54 referrer

Footnote 55

Ogle, J. W., G. P. Rabalais, and M. P. Glode. 1986. Duration of pharyngeal carriage of Haemophilus influenzae type b in children hospitalized with systemic infections. Pediatr. Infect. Dis. 5:509-511.

Return to footnote 55 referrer

Footnote 56

Powell, M., P. Seetulsingh, and J. D. Williams. 1989. In-vitro susceptibility of Haemophilus influenzae to meropenem compared with imipenem, five other beta-lactams, chloramphenicol and ciprofloxacin. J. Antimicrob. Chemother. 24 Suppl A:175-181.

Return to footnote 56 referrer

Footnote 57

Tristram, S., M. R. Jacobs, and P. C. Appelbaum. 2007. Antimicrobial resistance in Haemophilus influenzae. Clin. Microbiol. Rev. 20:368-389.

Return to footnote 57 referrer

Footnote 58

Pfaller, M. A., R. K. Flamm, R. E. Mendes, J. M. Streit, J. I. Smart, K. A. Hamed, L. R. Duncan, and H. S. Sader. 2018. Ceftobiprole Activity against Gram-Positive and -Negative Pathogens Collected from the United States in 2006 and 2016. Antimicrob. Agents Chemother. 63:e01566-18.

Return to footnote 58 referrer

Footnote 59

Sánchez Artola, B., and J. Barberán. 2017. Cefditoren: a reality for the treatment of community infections. Rev. Esp. Quimioter. 30:407-412.

Return to footnote 59 referrer

Footnote 60

Kaushik, D., S. Rathi, and A. Jain. 2011. Ceftaroline: a comprehensive update. Int. J. Antimicrob. Agents. 37:389-395.

Return to footnote 60 referrer

Footnote 61

Pfaller, M. A., D. J. Farrell, H. S. Sader, and R. N. Jones. 2012. AWARE Ceftaroline Surveillance Program (2008-2010): trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin. Infect. Dis. 55 Suppl 3:S187-93.

Return to footnote 61 referrer

Footnote 62

McCurdy, S., K. Keedy, L. Lawrence, A. Nenninger, A. Sheets, M. Quintas, and S. Cammarata. 2020. Efficacy of Delafloxacin versus Moxifloxacin against Bacterial Respiratory Pathogens in Adults with Community-Acquired Bacterial Pneumonia (CABP): Microbiology Results from the Delafloxacin Phase 3 CABP Trial. Antimicrob. Agents Chemother. 64:e01949-19.

Return to footnote 62 referrer

Footnote 63

Bhagwat, S. S., M. Nandanwar, A. Kansagara, A. Patel, S. Takalkar, R. Chavan, H. Periasamy, R. Yeole, P. K. Deshpande, S. Bhavsar, A. Bhatia, J. Ahdal, R. Jain, and M. Patel. 2019. Levonadifloxacin, a Novel Broad-Spectrum Anti-MRSA Benzoquinolizine Quinolone Agent: Review of Current Evidence. Drug Des. Devel. Ther. 13:4351-4365.

Return to footnote 63 referrer

Footnote 64

Pfaller, M. A., M. D. Huband, D. Shortridge, and R. K. Flamm. 2020. Surveillance of Omadacycline Activity Tested against Clinical Isolates from the United States and Europe: Report from the SENTRY Antimicrobial Surveillance Program, 2016 to 2018. Antimicrob. Agents Chemother. 64:e02488-19.

Return to footnote 64 referrer

Footnote 65

Pfaller, M. A., M. D. Huband, J. M. Streit, R. K. Flamm, and H. S. Sader. 2018. Surveillance of tigecycline activity tested against clinical isolates from a global (North America, Europe, Latin America and Asia-Pacific) collection (2016). Int. J. Antimicrob. Agents. 51:848-853.

Return to footnote 65 referrer

Footnote 66

Veeraraghavan, B., A. Poojary, C. Shankar, A. K. Bari, S. Kukreja, B. Thukkaram, R. G. Neethimohan, Y. D. Bakhtavachalam, and S. Kamat. 2019. In-vitro activity of tigecycline and comparator agents against common pathogens: Indian experience. J. Infect. Dev. Ctries. 13:245-250.

Return to footnote 66 referrer

Footnote 67

Zhao, C., X. Wang, Y. Zhang, R. Wang, Q. Wang, H. Li, and H. Wang. 2019. In vitro activities of Eravacycline against 336 isolates collected from 2012 to 2016 from 11 teaching hospitals in China. BMC Infect. Dis. 19:508-019-4093-1.

Return to footnote 67 referrer

Footnote 68

Matthews, D., O. Adegoke, and A. Shephard. 2020. Bactericidal activity of hexylresorcinol lozenges against oropharyngeal organisms associated with acute sore throat. BMC Res. Notes. 13:99-020-04954-1.

Return to footnote 68 referrer

Footnote 69

Lee, Y. R., and K. L. Jacobs. 2019. Leave it to Lefamulin: A Pleuromutilin Treatment Option in Community-Acquired Bacterial Pneumonia. Drugs. 79:1867-1876.

Return to footnote 69 referrer

Footnote 70

Hoban, D. J., G. V. Doern, A. C. Fluit, M. Roussel-Delvallez, and R. N. Jones. 2001. Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin. Infect. Dis. 32 Suppl 2:S81-93.

Return to footnote 70 referrer

Footnote 71

Heinz, E. 2018. The return of Pfeiffer's bacillus: Rising incidence of ampicillin resistance in Haemophilus influenzae. Microb. Genom. 4:e000214.

Return to footnote 71 referrer

Footnote 72

Wang, H. J., C. Q. Wang, C. Z. Hua, H. Yu, T. Zhang, H. Zhang, S. F. Wang, A. W. Lin, Q. Cao, W. C. Huang, H. L. Deng, S. C. Cao, and X. J. Chen. 2019. Antibiotic Resistance Profiles of Haemophilus influenzae Isolates from Children in 2016: A Multicenter Study in China. Can. J. Infect. Dis. Med. Microbiol. 2019:6456321.

Return to footnote 72 referrer

Footnote 73

Su, P. Y., A. H. Huang, C. H. Lai, H. F. Lin, T. M. Lin, and C. H. Ho. 2020. Extensively drug-resistant Haemophilus influenzae - emergence, epidemiology, risk factors, and regimen. BMC Microbiol. 20:102-020-01785-9.

Return to footnote 73 referrer

Footnote 74

Kaczmarek, F. S., T. D. Gootz, F. Dib-Hajj, W. Shang, S. Hallowell, and M. Cronan. 2004. Genetic and molecular characterization of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae with unusually high resistance to ampicillin. Antimicrob. Agents Chemother. 48:1630-1639.

Return to footnote 74 referrer

Footnote 75

Zhanel, G. G., L. Palatnick, K. A. Nichol, D. E. Low, D. J. Hoban, and CROSS Study Group. 2003. Antimicrobial resistance in Haemophilus influenzae and Moraxella catarrhalis respiratory tract isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob. Agents Chemother. 47:1875-1881.

Return to footnote 75 referrer

Footnote 76

Yamada, S., S. Seyama, T. Wajima, Y. Yuzawa, M. Saito, E. Tanaka, and N. Noguchi. 2020. β-Lactamase-non-producing ampicillin-resistant Haemophilus influenzae is acquiring multidrug resistance. J. Infect. Public. Health. 13:497-501.

Return to footnote 76 referrer

Footnote 77

McDonnell, G., and A. D. Russell. 1999. Antiseptics and disinfectants: activity, action, and resistance. Clin. Microbiol. Rev. 12:147-179.

Return to footnote 77 referrer

Footnote 78

Rodríguez Ferri, E. F., S. Martínez, R. Frandoloso, S. Yubero, and C. B. Gutiérrez Martín. 2010. Comparative efficacy of several disinfectants in suspension and carrier tests against Haemophilus parasuis serovars 1 and 5. Res. Vet. Sci. 88:385-389.

Return to footnote 78 referrer

Footnote 79

Farkas, J. 1998. Irradiation as a method for decontaminating food. A review. Int. J. Food Microbiol. 44:189-204.

Return to footnote 79 referrer

Footnote 80

Yin, R., T. Dai, P. Avci, A. E. Jorge, W. C. de Melo, D. Vecchio, Y. Y. Huang, A. Gupta, and M. R. Hamblin. 2013. Light based anti-infectives: ultraviolet C irradiation, photodynamic therapy, blue light, and beyond. Curr. Opin. Pharmacol. 13:731-762.

Return to footnote 80 referrer

Footnote 81

Hancock, C. O. 2013. Heat Sterilization, p. 277. A. P. Fraise, J. Y. Mailard, and S. A. Sattar (eds.), Russell, Hugo & Ayliffe’s: Principles and Practice of Disinfection, Preservation and Sterilization, Fifth ed., . Blackwell Publishing Ltd.

Return to footnote 81 referrer

Footnote 82

Murphy, T. V., J. F. Clements, M. Petroni, S. Coury, and L. Stetler. 1989. Haemophilus influenzae type b in respiratory secretions. Pediatr. Infect. Dis. J. 8:148-151.

Return to footnote 82 referrer

Footnote 83

Mitscherlich, E., and E. H. Marth. 1984. Microbial Survival in the Environment. Springer.

Return to footnote 83 referrer

Footnote 84

Albuquerque, R. C., A. C. R. Moreno, S. R. Dos Santos, S. L. B. Ragazzi, and M. B. Martinez. 2019. Multiplex-PCR for diagnosis of bacterial meningitis. Braz J. Microbiol. 50:435-443.

Return to footnote 84 referrer

Footnote 85

Hu, L., B. Han, Q. Tong, H. Xiao, and D. Cao. 2020. Detection of Eight Respiratory Bacterial Pathogens Based on Multiplex Real-Time PCR with Fluorescence Melting Curve Analysis. Can. J. Infect. Dis. Med. Microbiol. 2020:2697230.

Return to footnote 85 referrer

Footnote 86

Munson, E. L., and G. V. Doern. 2007. Comparison of three commercial test systems for biotyping Haemophilus influenzae and Haemophilus parainfluenzae. J. Clin. Microbiol. 45:4051-4053.

Return to footnote 86 referrer

Footnote 87

Van Damme, P., G. Leroux-Roels, C. Vandermeulen, I. De Ryck, A. Tasciotti, M. Dozot, L. Moraschini, M. Testa, and A. K. Arora. 2019. Safety and immunogenicity of non-typeable Haemophilus influenzae-Moraxella catarrhalis vaccine. Vaccine. 37:3113-3122.

Return to footnote 87 referrer

Footnote 88

Prymula, R., P. Peeters, V. Chrobok, P. Kriz, E. Novakova, E. Kaliskova, I. Kohl, P. Lommel, J. Poolman, J. P. Prieels, and L. Schuerman. 2006. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet. 367:740-748.

Return to footnote 88 referrer

Footnote 89

Clarke, C., L. O. Bakaletz, J. Ruiz-Guiñazú, D. Borys, and T. Mrkvan. 2017. Impact of protein D-containing pneumococcal conjugate vaccines on non-typeable Haemophilus influenzae acute otitis media and carriage. Expert Rev. Vaccines. 16:1-14.

Return to footnote 89 referrer

Footnote 90

Novotny, L. A., and L. O. Bakaletz. 2020. Transcutaneous immunization with a nontypeable Haemophilus influenzae dual adhesin-directed immunogen induces durable and boostable immunity. Vaccine. 38:2378-2386.

Return to footnote 90 referrer

Footnote 91

Jacobson, J. T., R. B. Orlob, and J. L. Clayton. 1985. Infections acquired in clinical laboratories in Utah. J. Clin. Microbiol. 21:486-489.

Return to footnote 91 referrer

Footnote 92

Pike, R. M. 1976. Laboratory-associated infections: summary and analysis of 3921 cases. Health Lab. Sci. 13:105-114.

Return to footnote 92 referrer

Footnote 93

Public Health Agency of Canada. 2019. ePATHogen - Risk Group Database. 2019:.

Return to footnote 93 referrer

Footnote 94

Public Health Agency of Canada. 2019. Human Pathogens and Toxins Act (HPTA) (S.C. 2009, c.24).

Return to footnote 94 referrer

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