Microbiology, epidemiology and treatment of Haemophilus inuenzae

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Official reprint from UpToDate www.uptodate.com 2014 UpToDate

Microbiology, epidemiology and treatment of Haemophilus influenzae Author Sylvia Yeh, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2014. | This topic last updated: Mar 21, 2014. INTRODUCTION Haemophilus influenzae colonizes the human respiratory tract and is transmitted from person to person via airborne droplets and direct contact with respiratory secretions [1]. H. influenzae has encapsulated (serotypes a through f) and nonencapsulated forms (nontypeable). The most important serotype is H. influenzae serotype b (Hib), which was a frequent cause of bacteremia, meningitis, and other invasive infections prior to the routine use of Hib conjugate vaccines in children [2]. Other capsular serotypes and unencapsulated H. influenzae strains can also cause disease, mainly mucosal infections (sinusitis, otitis, bronchitis, and pneumonia), but occasionally cause more invasive infections. The bacteriology, epidemiology, and treatment of H. influenzae are reviewed here. H. influenzae infections in children and prevention of H. influenzae are discussed separately. (See "Prevention of Haemophilus influenzae infection".) MICROBIOLOGY H. influenzae are small, pleomorphic gram-negative rods that are oxidase-positive, facultatively anaerobic, and nonmotile. In clinical specimens obtained from patients who have received beta-lactam antibiotics, H. influenzae can appear as filamentous rods. In vitro growth requires a CO2-enriched atmosphere, hemin (factor X), and nicotinamide adenine dinucleotide (NAD, factor V); therefore, isolation from clinical specimens on solid medium requires the use of chocolate agar or other X and V factor supplemented media. H. influenzae appear as transparent or slightly opaque colonies on solid media. Capsule The presence or absence of a polysaccharide capsule is an important distinguishing characteristic of H. influenzae species. The polysaccharide capsule can be serologically classified into six serotypes (a through f), while H. influenzae lacking a polysaccharide capsule are considered to be nontypeable [3]. The type b capsule consists of a ribosyl and ribitol phosphate polymer and is the primary antigenic constituent of polysaccharide and polysaccharide conjugate Hib vaccines [2]. Nontypeable strains are genetically heterogeneous; some carry genetic elements for capsule production that are not expressed, while other isolates do not have any of these genes and are more distantly related [3]. Even among identically classified nontypeable strains, electrophoresis of outer membrane proteins or enzymatic analysis demonstrates great heterogeneity of nonencapsulated strains. Infections of the upper and lower respiratory tract are largely caused by nontypeable strains. Nontypeable strains have been classified into eight biotypes based upon the presence or absence of indole, urease, and ornithine decarboxylase. Some biotypes have been associated with specific clinical syndromes; H. influenzae biotype 3 isolates (also known as biotype aegyptius) are associated with the syndrome of Brazilian purpuric fever [4], and biotype 4 isolates are associated with maternal genitourinary tract infections and neonatal sepsis [5,6]. Section Editor Daniel J Sexton, MD Deputy Editor Anna R Thorner, MD

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Outer membrane proteins The outer membrane of H. influenzae contains several proteins enabling attachment to epithelial cells and facilitating colonization of the human respiratory tract. These include pili, fimbriae, high molecular weight factors (HMW1 and HMW2), and Hia (homologous to the pertussis hemagglutinin). Pili seem to be required for adherence to respiratory mucin and pharyngeal colonization, while the other adhesins may be more influential in the pathogenesis of otitis media [7-10]. A study of strains lacking the pili structural genes (hifA) demonstrated diminished bacterial adherence to mucin; antibodies to hifA also blocked adherence [9]. In a report of 17 nasopharyngeal and middle ear isolates, most expressed HMW1 or HMW2, while only a few nasopharyngeal isolates expressed pili or Hia [8]. Lipopolysaccharide (LPS) is also a component of the H. influenzae outer membrane that contributes to pathogen structural integrity and elicits a potent endotoxin host inflammatory response. Hib LPS has limited antigenic diversity, although variability in LPS electrophoretic patterns occurs with passage in vivo or in vitro, making electrophoresis of LPS a less useful epidemiologic tool [11]. When injected, Hib LPS produces a dermal Shwartzman reaction, is lethal in mice, causes a febrile response, and evokes polyclonal B-cell activation in rabbits [1,12]. IgA proteases Given the important role of IgA in mucosal defense, bacterial IgA proteases are likely important virulence factors. H. influenzae produces three types of IgA proteases that cleave different peptide bonds within the IgA1 hinge region [13]. Intracellular survival H. influenzae can survive within respiratory epithelial cells; this intracellular sequestration may explain the ability of these organisms to colonize the respiratory epithelium for extended periods [14]. Furthermore, H. influenzae can gain access to the subepithelial space, either by transmural migration across epithelial cells or by an independent intercellular mechanism. This provides access to the vascular system, which can lead to bacteremia and metastatic infection, including meningitis. EPIDEMIOLOGY By 18 months of age, one-third of children have had H. influenzae nasopharyngeal colonization with both typeable and nontypeable H. influenzae [7,15]. Carriage rates in households or daycare centers with an index case can exceed 60 percent [8,16]. Colonization can persist for months, and intercurrent upper respiratory infection may promote invasive disease as well as enhance spread among close contacts [9,15,17-19]. Simultaneous colonization by multiple strains is common, and longitudinal monitoring demonstrates that colonization is a dynamic process with a turnover of individual strains over time [19]. Since the introduction of Hib conjugate vaccines in 1985, the incidence of invasive disease cause by H. influenzae in the United States has decreased dramatically. Between 1989 and 2008, 7559 cases of H. influenzae disease were reported in the United States; the estimated mean annual incidence was 1.62 per 100,000 population, and 15 percent of cases were fatal [20]. A considerable burden of non-Hib disease is still present in the oldest and youngest age groups. The largest burden of disease among children occurred in infants <1 year; many of these cases occurred during the first month of life in preterm or low birth weight infants. H. influenzae serotype b H. influenzae is an exclusively human pathogen; it is transmitted from person to person via airborne droplets and direct contact with respiratory secretions [1]. Prior to the routine use of H. influenzae serotype b (Hib) conjugate vaccines in infants, invasive Hib was the leading cause of bacterial meningitis in children; 85 percent of these infections occurred in children under five years of age [21]. Hib was also a leading cause of epiglottitis, pneumonia, empyema, pericarditis, bacteremia, and septic arthritis. Clinical manifestations of invasive Hib infections reflect the organism's capacity for vascular invasion and establishing metastatic foci of infection including meningitis, septic arthritis, osteomyelitis, and cellulitis [14]. Prior to routine vaccination, the incidence of invasive Hib disease varied from 67 to 130 cases per 100,000 children under five years per year, and the incidence of Hib meningitis was 40 to 69 cases per 100,000 children per year. This incidence was equivalent to approximately 25,000 cases of acquired invasive Hib annually in the United States, or

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invasive infection in 1 per 200 children in the first five years of life [22]. Some populations at increased risk had incidence up to four times this rate. Before widespread immunization, the secondary attack rate among children who were household contacts of an index case was 0.3 percent, which is 500-fold higher than the age-adjusted risk in the general population [19]. This risk of secondary infection increased inversely with age; children under four years of age were at greatest risk, and clinical disease was most likely in the first 30 days after exposure to the index case [23-29]. However, the widespread use of conjugate Hib vaccines in infancy has resulted in a dramatic decline in invasive Hib disease in children to one case or less per 100,000 [4,30]. The incidence of invasive disease among individuals over five years of age has been stable at approximately 0.5 per 100,000 population. Hib immunization has reduced carriage (and presumably transmission) and facilitated herd immunity. This reduction in carriage seems to be influenced by number and type of Hib immunizations as well as time post immunization. Consequently, the differences in immunization schedules internationally may result in differing carriage and disease patterns. In England following a period of time when only infant Hib vaccination was practiced (without a toddler booster), there was waning immunity and some recurrence of Hib disease among toddlers. Investigators found that the point prevalence of Hib carriage among 855 British children ages 6 to 16 during this period (between 1999 and 2003) remained high (4 percent) [31]. The global burden of Hib disease is substantial; worldwide Hib caused about 8.13 million serious illnesses worldwide in 2000, with 371,000 deaths [32]. This is almost entirely vaccine preventable; expanded use of the Hib vaccine could reduce pneumonia, meningitis, and mortality among children. Most cases of invasive H. influenzae infection since introduction of the Hib vaccination have been attributable to nontype B strains [21,33]. Some reports of invasive H. influenzae from areas with widespread Hib conjugate vaccination have identified serotype f and nontypeable H. influenzae as being the most common of the invasive isolates, with one series reporting serotype a predominately in children [34-36]. Children who experience Hib disease despite vaccination may have an immunologic defect impairing production of memory B cells [37]. Nontypeable H. influenzae Nontypeable H. influenzae (NTHi) is a common commensal constituent of the nasopharyngeal flora [38,39]. Approximately 20 percent of infants are colonized in the first year of life, and more than one-half of children are colonized by age five [40]. Children may be colonized by multiple distinct strains at a given time, and colonizing strains may change over time [41-43]. Colonization persists throughout adulthood [40,44,45]. NTHi causes noninvasive infections in older children and adults, usually as a result of local spread of organisms from the nasopharynx [46]. It is an important cause of sinusitis, otitis media, conjunctivitis, bronchitis, pneumonia and bacteremia, and posttraumatic meningitis [3,5,18,47-53]. In a report of 157 cases of otitis media, for example, NTHi accounted for about 30 percent of cases [53]. The density of NTHi colonization has been correlated with increased rates of otitis media, although no correlation has been established between the duration of NTHi colonization and the risk of otitis media [54,55]. (See "Acute otitis media in children: Epidemiology, microbiology, clinical manifestations, and complications", section on 'Bacteria'.) NTHi can cause community-acquired pneumonia in adults and may be associated with severe disease and high mortality in higher risk populations. Although bacteremia that complicates H. influenzae pneumonia occurs occasionally, disseminated infections following nontypeable H. influenzae bacteremia are uncommon except in newborns and immunocompromised patients. Nontypeable H. influenzae can also colonize the female genital tract and cause locally invasive disease such as endometritis, amnionitis, or Bartholin gland abscess, with or without accompanying bacteremia [6]. Risk factors In addition to age, factors conferring increased risk for H. influenzae infection include underlying
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immunocompromising conditions such as complement deficiency, hypogammaglobulinemia, sickle cell anemia, functional asplenia, malignancy, and HIV [16,19,56-60]. In adults, underlying conditions such as chronic pulmonary disease, smoking, HIV, alcoholism, pregnancy, malignancy, and older age increase the risk of H. influenzae disease [6167]. Among pregnant women, invasive infection with unencapsulated H. influenzae has been associated with preterm birth and fetal loss [67]. Socioeconomic risk factors that increase risk of H. influenzae disease include crowding, poor immunization, and daycare attendance [19,56,68]. Native American and aboriginal groups are also at increased risk for invasive H. influenzae disease [58,69]. In an Australian review of bacterial meningitis, for example, the annual incidence rate of H. influenzae was significantly higher in Aboriginal than non-Aboriginal children (150 versus 27 per 100,000 persons) [58]. Socioeconomic, environmental, microbiologic, and genetic factors may play an important role in these observations. IMMUNITY Both innate and acquired humoral immunity play important roles in host defense against invasive H. influenzae. Newborns are protected against Hib via maternal antibodies, but they are susceptible to infection with nontypeable (unencapsulated) strains [51]. Breast feeding affords some protection against H. influenzae [57]. As maternal antibody levels wane, children become susceptible to invasive Hib infection from around age three months to three years. Prior to the routine use of Hib conjugate vaccines, children older than three years of age progressively gained protection against invasive disease with repeated exposure and subsequent nasopharyngeal colonization. The decline in individual serum anti-Hib antibody levels observed since introduction of Hib vaccination suggests that ongoing antigen exposure in the setting of Hib colonization may play a role Hib immunity [51,52]. The opsonization of H. influenzae by C3 and subsequent phagocytosis appears to be more important than direct complement-mediated lysis. This understanding is based upon the clinical observation that individuals with deficiencies of early complement components are at increased risk for H. influenzae infections, while those with deficiencies of terminal complement components do not experience heightened susceptibility to the organism [70]. H. influenzae lipooligosaccharide (LOS) activates the alternative complement pathway to generate C3b, an important opsonin. Anticapsular antibodies, particularly of the IgG1 subclass, bind to the polysaccharide capsule and activate the classical complement pathway. TREATMENT The treatment of specific syndromes attributable to H. influenzae is discussed in detail separately. In general, beta-lactam agents (eg, amoxicillin or a second- or third-generation cephalosporin) are the preferred antimicrobial agents if the organism is susceptible (table 1). Alternative agents with activity against H. influenzae include fluoroquinolones, macrolides, tetracyclines, and aminoglycosides. Among the macrolides, azithromycin is more active in vitro against most strains of H. influenzae and has more rapid killing and a longer post-antibiotic effect than clarithromycin [71,72]. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization" and "Antibiotic studies for the treatment of community-acquired pneumonia in adults" and "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Haemophilus influenzae' and "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'H. influenzae type b' and "Epiglottitis (supraglottitis): Treatment and prevention".) BLNAR and beta-lactam-resistant H. influenzae Beta-lactamasenegative, ampicillin-resistant (BLNAR) H. influenzae is an emerging pathogen. The prevalence of BLNAR H. influenzae strains has increased in Japan (approximately 34 percent) [48], Spain (approximately 56 percent) [49], and other parts of Europe and Canada [73]. Prevalence in the United States has remained low (approximately 3 percent) [50]. Possible explanations for this observation include inadequate vaccination against H. influenzae type b in some regions, increasingly frequent use of cephalosporins, and underdosing of oral ampicillin [48,50]. There are no significant differences in the clinical presentation of pneumonia due to BLNAR H. influenzae compared to pneumonia due to ampicillin-susceptible H. influenzae strains.
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These pathogens appear to be susceptible in vitro to ceftriaxone [74]. Depending on local susceptibility findings, ceftriaxone may be an appropriate choice for treatment of clinical infections due to BLNAR H. influenzae pending further study of clinical infections with this pathogen. There have also been reports of increased prevalence of nontypeable H. influenzae strains with resistance to ampicillin and/or other beta-lactams. In a retrospective study that evaluated 465 H. influenzae isolates from the blood or cerebrospinal fluid from patients in Sweden between 1997 and 2010, a significant increase in beta-lactamasenegative, beta-lactamresistant isolates was observed over the course of the study period. Ninety-one isolates (20 percent) were beta-lactam resistant (defined as resistance to one or more beta-lactam, including penicillin, ampicillin, a cephalosporin, or a carbapenem), of which 43 (10 percent) were beta-lactamase negative and beta-lactam resistant. [75] SUMMARY AND RECOMMENDATIONS ! Haemophilus influenzae colonizes the human respiratory tract and is transmitted from person to person via airborne droplets and direct contact with respiratory secretions. (See 'Introduction' above.) ! H. influenzae are small, pleomorphic gram-negative rods that are oxidase-positive, facultatively anaerobic, and nonmotile. The presence or absence of a polysaccharide capsule is an important distinguishing characteristic of H. influenzae species. The polysaccharide capsule can be serologically classified into six serotypes (a through f), while H. influenzae lacking a polysaccharide capsule are considered to be nontypeable. (See 'Microbiology' above.) ! By 18 months of age, one-third of children have had H. influenzae nasopharyngeal colonization with both typeable and nontypeable H. influenzae. Carriage rates in households or daycare centers with an index case can exceed 60 percent. Colonization can persist for months, and intercurrent upper respiratory infection may promote invasive disease as well as enhance spread among close contacts. (See 'Epidemiology' above.) ! Prior to the routine use of H. influenzae serotype b (Hib) conjugate vaccines in infants, invasive Hib was the leading cause of bacterial meningitis in children; 85 percent of these infections occurred in children under five years of age. Hib was also a leading cause of epiglottitis, pneumonia, empyema, pericarditis, bacteremia, and septic arthritis. Clinical manifestations of invasive Hib infections reflect the organism's capacity for vascular invasion and establishing metastatic foci of infection including meningitis, septic arthritis, osteomyelitis, and cellulitis. Most cases of invasive H. influenzae infection since introduction of the Hib vaccination have been attributable to non-type B strains. (See 'H. influenzae serotype b' above.) ! Nontypeable H. influenzae can cause community-acquired pneumonia in adults and may be associated with severe disease and high mortality in higher risk populations. Although bacteremia that complicates H. influenzae pneumonia occurs occasionally, disseminated infections following nontypeable H. influenzae bacteremia are uncommon, except in newborns and immunocompromised patients. Nontypeable H. influenzae can also colonize the female genital tract and cause locally invasive disease, such as endometritis, amnionitis, or Bartholin gland abscess, with or without accompanying bacteremia. (See 'Nontypeable H. influenzae' above.) ! In addition to age, factors conferring increased risk for H. influenzae infection include underlying immunocompromising conditions, including complement deficiency, hypogammaglobulinemia, sickle cell anemia, functional asplenia, malignancy, and HIV. In adults, underlying conditions, such as chronic pulmonary disease, smoking, HIV, alcoholism, pregnancy, malignancy, and older age, increase the risk of H. influenzae disease. Socioeconomic risk factors that increase risk include crowding, poor immunization, and daycare attendance. (See 'Risk factors' above.) ! The treatment of specific syndromes attributable to H. influenzae is discussed in detail separately. In general, betalactam agents (eg, penicillins, such as amoxicillin, or second or third-generation cephalosporins) are the preferred
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antimicrobial agents if the organism is susceptible (table 1). Alternative agents with activity against H. influenzae include fluoroquinolones, macrolides, tetracyclines, and aminoglycosides. Among the macrolides, azithromycin is more active in vitro against most strains of H. influenzae than clarithromycin. (See 'Treatment' above and "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of communityacquired pneumonia in adults who require hospitalization" and "Antibiotic studies for the treatment of communityacquired pneumonia in adults" and "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Haemophilus influenzae' and "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'H. influenzae type b' and "Epiglottitis (supraglottitis): Treatment and prevention".) ! Beta-lactamasenegative, ampicillin-resistant (BLNAR) H. influenzae is an emerging pathogen in certain regions, such as Japan and Spain, although its prevalence in the United States and elsewhere remains low. These pathogens appear to be susceptible in vitro to ceftriaxone. There have also been reports of increased prevalence of nontypeable H. influenzae strains with resistance to ampicillin and/or other beta-lactams. (See 'BLNAR and beta-lactam-resistant H. influenzae' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Ward JI, Zangwill KM. Haemophilus influenzae vaccines. In: Vaccines, 3, Plotkin SA, Orienstein WA (Eds), WB Saunders Company, Philadelphia 1999. 2. Eskola J, Kyhty H, Takala AK, et al. A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus influenzae type b disease. N Engl J Med 1990; 323:1381. 3. St Geme JW 3rd, Takala A, Esko E, Falkow S. Evidence for capsule gene sequences among pharyngeal isolates of nontypeable Haemophilus influenzae. J Infect Dis 1994; 169:337. 4. Segada LM, Carlone GM, Gheesling LL, Lesse AJ. Characterization of P1-deficient isogenic mutant of Haemophilus influenzae biogroup aegyptius associated with Brazilian purpuric fever. Microb Pathog 2000; 28:145. 5. Quentin R, Musser JM, Mellouet M, et al. Typing of urogenital, maternal, and neonatal isolates of Haemophilus influenzae and Haemophilus parainfluenzae in correlation with clinical source of isolation and evidence for a genital specificity of H. influenzae biotype IV. J Clin Microbiol 1989; 27:2286. 6. Wallace RJ Jr, Baker CJ, Quinones FJ, et al. Nontypable Haemophilus influenzae (biotype 4) as a neonatal, maternal, and genital pathogen. Rev Infect Dis 1983; 5:123. 7. Rao VK, Krasan GP, Hendrixson DR, et al. Molecular determinants of the pathogenesis of disease due to nontypable Haemophilus influenzae. FEMS Microbiol Rev 1999; 23:99. 8. Krasan GP, Cutter D, Block SL, St Geme JW 3rd. Adhesin expression in matched nasopharyngeal and middle ear isolates of nontypeable Haemophilus influenzae from children with acute otitis media. Infect Immun 1999; 67:449. 9. Kubiet M, Ramphal R, Weber A, Smith A. Pilus-mediated adherence of Haemophilus influenzae to human respiratory mucins. Infect Immun 2000; 68:3362. 10. St Geme JW 3rd. Insights into the mechanism of respiratory tract colonization by nontypable Haemophilus influenzae. Pediatr Infect Dis J 1997; 16:931. 11. Whisnant JK, Rogentine GN, Mann DL, Robbins JB. Human cell-surface structures related to Haemophilus influenzae type B disease. Lancet 1971; 2:895. 12. Miragliotta G, Colucci M, Semeraro N, et al. Platelet injury and stimulation of leukocyte procoagulant activity in vitro by a lipopolysaccharide from Haemophilus influenzae type b. Microbiologica 1981; 4:173. 13. Plaut AG. The IgA1 proteases of pathogenic bacteria. Annu Rev Microbiol 1983; 37:603. 14. Moxon ER. Molecular basis of invasive Haemophilus influenzae type b disease. J Infect Dis 1992; 165 Suppl 1:S77.
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15. Aniansson G, Alm B, Andersson B, et al. Nasopharyngeal colonization during the first year of life. J Infect Dis 1992; 165 Suppl 1:S38. 16. Shapiro ED, Ward JI. The epidemiology and prevention of disease caused by Haemophilus influenzae type b. Epidemiol Rev 1991; 13:113. 17. Krasinski K, Nelson JD, Butler S, et al. Possible association of mycoplasma and viral respiratory infections with bacterial meningitis. Am J Epidemiol 1987; 125:499. 18. Takala AK, Meurman O, Kleemola M, et al. Preceding respiratory infection predisposing for primary and secondary invasive Haemophilus influenzae type b disease. Pediatr Infect Dis J 1993; 12:189. 19. Mkel PH, Takala AK, Peltola H, Eskola J. Epidemiology of invasive Haemophilus influenzae type b disease. J Infect Dis 1992; 165 Suppl 1:S2. 20. MacNeil JR, Cohn AC, Farley M, et al. Current epidemiology and trends in invasive Haemophilus influenzae disease--United States, 1989-2008. Clin Infect Dis 2011; 53:1230. 21. Wenger JD, Hightower AW, Facklam RR, et al. Bacterial meningitis in the United States, 1986: report of a multistate surveillance study. The Bacterial Meningitis Study Group. J Infect Dis 1990; 162:1316. 22. Cochi SL, Broome CV. Vaccine prevention of Haemophilus influenzae type b disease: past, present and future. Pediatr Infect Dis 1986; 5:12. 23. Ward JI, Fraser DW, Baraff LJ, Plikaytis BD. Haemophilus influenzae meningitis. A national study of secondary spread in household contacts. N Engl J Med 1979; 301:122. 24. Recommendations for use of Haemophilus b conjugate vaccines and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine. Recommendations of the advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1993; 42:1. 25. Band JD, Fraser DW, Ajello G. Prevention of Hemophilus influenzae type b disease. JAMA 1984; 251:2381. 26. Fleming DW, Leibenhaut MH, Albanes D, et al. Secondary Haemophilus influenzae type b in day-care facilities. Risk factors and prevention. JAMA 1985; 254:509. 27. Makintubee S, Istre GR, Ward JI. Transmission of invasive Haemophilus influenzae type b disease in day care settings. J Pediatr 1987; 111:180. 28. Osterholm MT, Pierson LM, White KE, et al. The risk of subsequent transmission of Hemophilus influenzae type B disease among children in day care. Results of a two-year statewide prospective surveillance and contact survey. N Engl J Med 1987; 316:1. 29. Murphy TV, Clements JF, Breedlove JA, et al. Risk of subsequent disease among day-care contacts of patients with systemic Hemophilus influenzae type B disease. N Engl J Med 1987; 316:5. 30. Centers for Disease Control and Prevention (CDC). Progress toward eliminating Haemophilus influenzae type b disease among infants and children--United States, 1987-1997. MMWR Morb Mortal Wkly Rep 1998; 47:993. 31. Oh SY, Griffiths D, John T, et al. School-aged children: a reservoir for continued circulation of Haemophilus influenzae type b in the United Kingdom. J Infect Dis 2008; 197:1275. 32. Watt JP, Wolfson LJ, O'Brien KL, et al. Burden of disease caused by Haemophilus influenzae type b in children younger than 5 years: global estimates. Lancet 2009; 374:903. 33. Heath PT, Booy R, Azzopardi HJ, et al. Non-type b Haemophilus influenzae disease: clinical and epidemiologic characteristics in the Haemophilus influenzae type b vaccine era. Pediatr Infect Dis J 2001; 20:300. 34. Adam HJ, Richardson SE, Jamieson FB, et al. Changing epidemiology of invasive Haemophilus influenzae in Ontario, Canada: evidence for herd effects and strain replacement due to Hib vaccination. Vaccine 2010; 28:4073. 35. Bender JM, Cox CM, Mottice S, et al. Invasive Haemophilus influenzae disease in Utah children: an 11-year population-based study in the era of conjugate vaccine. Clin Infect Dis 2010; 50:e41. 36. Resman F, Ristovski M, Ahl J, et al. Invasive disease caused by Haemophilus influenzae in Sweden 1997-2009; evidence of increasing incidence and clinical burden of non-type b strains. Clin Microbiol Infect 2011; 17:1638. 37. Lee YC, Kelly DF, Yu LM, et al. Haemophilus influenzae type b vaccine failure in children is associated with inadequate production of high-quality antibody. Clin Infect Dis 2008; 46:186.

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38. St Geme JW 3rd. Molecular and cellular determinants of non-typeable Haemophilus influenzae adherence and invasion. Cell Microbiol 2002; 4:191. 39. Murphy TF, Faden H, Bakaletz LO, et al. Nontypeable Haemophilus influenzae as a pathogen in children. Pediatr Infect Dis J 2009; 28:43. 40. Howard AJ, Dunkin KT, Millar GW. Nasopharyngeal carriage and antibiotic resistance of Haemophilus influenzae in healthy children. Epidemiol Infect 1988; 100:193. 41. Spinola SM, Peacock J, Denny FW, et al. Epidemiology of colonization by nontypable Haemophilus influenzae in children: a longitudinal study. J Infect Dis 1986; 154:100. 42. Trottier S, Stenberg K, Svanborg-Edn C. Turnover of nontypable Haemophilus influenzae in the nasopharynges of healthy children. J Clin Microbiol 1989; 27:2175. 43. Faden H, Duffy L, Williams A, et al. Epidemiology of nasopharyngeal colonization with nontypeable Haemophilus influenzae in the first 2 years of life. J Infect Dis 1995; 172:132. 44. Faden H, Waz MJ, Bernstein JM, et al. Nasopharyngeal flora in the first three years of life in normal and otitisprone children. Ann Otol Rhinol Laryngol 1991; 100:612. 45. Kuklinska D, Kilian M. Relative proportions of Haemophilus species in the throat of healthy children and adults. Eur J Clin Microbiol 1984; 3:249. 46. Farley MM, Stephens DS, Brachman PS Jr, et al. Invasive Haemophilus influenzae disease in adults. A prospective, population-based surveillance. CDC Meningitis Surveillance Group. Ann Intern Med 1992; 116:806. 47. Sez-Llorens X. Pathogenesis of acute otitis media. Pediatr Infect Dis J 1994; 13:1035. 48. Hasegawa K, Kobayashi R, Takada E, et al. High prevalence of type b beta-lactamase-non-producing ampicillinresistant Haemophilus influenzae in meningitis: the situation in Japan where Hib vaccine has not been introduced. J Antimicrob Chemother 2006; 57:1077. 49. Garca-Cobos S, Campos J, Lzaro E, et al. Ampicillin-resistant non-beta-lactamase-producing Haemophilus influenzae in Spain: recent emergence of clonal isolates with increased resistance to cefotaxime and cefixime. Antimicrob Agents Chemother 2007; 51:2564. 50. Nakamura S, Yanagihara K, Seki M, et al. Clinical characteristics of pneumonia caused by beta-lactamase negative ampicillin resistant Haemophilus influenzae (BLNAR). Scand J Infect Dis 2007; 39:521. 51. Falla TJ, Dobson SR, Crook DW, et al. Population-based study of non-typable Haemophilus influenzae invasive disease in children and neonates. Lancet 1993; 341:851. 52. Winkelstein JA, Moxon ER. The role of complement in the host's defense against Haemophilus influenzae. J Infect Dis 1992; 165 Suppl 1:S62. 53. Harabuchi Y, Faden H, Yamanaka N, et al. Nasopharyngeal colonization with nontypeable Haemophilus influenzae and recurrent otitis media. Tonawanda/Williamsville Pediatrics. J Infect Dis 1994; 170:862. 54. Faden H, Stanievich J, Brodsky L, et al. Changes in nasopharyngeal flora during otitis media of childhood. Pediatr Infect Dis J 1990; 9:623. 55. Long SS, Henretig FM, Teter MJ, McGowan KL. Nasopharyngeal flora and acute otitis media. Infect Immun 1983; 41:987. 56. Michaels RH, Schultz WF. The frequency of Haemophilus influenzae infections: Analysis of racial and environmental factors. In: Haemophilus influenzae, Sell SH, Karson DT (Eds), Vanderbilt University Press, Nashville 1973. p.243. 57. Petersen GM, Silimperi DR, Chiu CY, Ward JI. Effects of age, breast feeding, and household structure on Haemophilus influenzae type b disease risk and antibody acquisition in Alaskan Eskimos. Am J Epidemiol 1991; 134:1212. 58. Hanna JN, Wild BE. Bacterial meningitis in children under five years of age in Western Australia. Med J Aust 1991; 155:160. 59. Muoz P, Miranda ME, Llancaqueo A, et al. Haemophilus species bacteremia in adults. The importance of the human immunodeficiency virus epidemic. Arch Intern Med 1997; 157:1869. 60. Cordero E, Pachn J, Rivero A, et al. Haemophilus influenzae pneumonia in human immunodeficiency virushttp://www.uptodate.com/contents/microbiology-epidemiology-and-treatilus+inuenzae&selectedTitle=1%7E150&view=print&displayedView=full Page 8 of 12

Microbiology, epidemiology and treatment of Haemophilus inuenzae

4/22/14, 21:22

infected patients. The Grupo Andaluz para el Estudio de las Enfermedades Infecciosas. Clin Infect Dis 2000; 30:461. 61. Mller LV, Regelink AG, Grasselier H, et al. Multiple Haemophilus influenzae strains and strain variants coexist in the respiratory tract of patients with cystic fibrosis. J Infect Dis 1995; 172:1388. 62. Powars D, Overturf G, Turner E. Is there an increased risk of Haemophilus influenzae septicemia in children with sickle cell anemia? Pediatrics 1983; 71:927. 63. Chilcote RR, Baehner RL, Hammond D. Septicemia and meningitis in children splenectomized for hodgkin's disease. N Engl J Med 1976; 295:798. 64. Farrand RJ. Recurrent haemophilus septicaemia and immunoglobulin deficiency. Arch Dis Child 1970; 45:582. 65. Miravitlles M, Espinosa C, Fernndez-Laso E, et al. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest 1999; 116:40. 66. Murphy TF. Haemophilus influenzae in chronic bronchitis. Semin Respir Infect 2000; 15:41. 67. Collins S, Ramsay M, Slack MP, et al. Risk of invasive Haemophilus influenzae infection during pregnancy and association with adverse fetal outcomes. JAMA 2014; 311:1125. 68. Rello J, Rodriguez R, Jubert P, Alvarez B. Severe community-acquired pneumonia in the elderly: epidemiology and prognosis. Study Group for Severe Community-Acquired Pneumonia. Clin Infect Dis 1996; 23:723. 69. Brown VM, Madden S, Kelly L, et al. Invasive Haemophilus influenzae disease caused by non-type b strains in Northwestern Ontario, Canada, 2002-2008. Clin Infect Dis 2009; 49:1240. 70. Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 1991; 4:359. 71. Zuckerman JM. Macrolides and ketolides: azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am 2004; 18:621. 72. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27. 73. Ladhani S, Slack MP, Heath PT, et al. Invasive Haemophilus influenzae Disease, Europe, 1996-2006. Emerg Infect Dis 2010; 16:455. 74. Ohno A, Ishii Y, Kobayashi I, Yamaguchi K. Antibacterial activity and PK/PD of ceftriaxone against penicillinresistant Streptococcus pneumoniae and beta-lactamase-negative ampicillin-resistant Haemophilus influenzae isolates from patients with community-acquired pneumonia. J Infect Chemother 2007; 13:296. 75. Resman F, Ristovski M, Forsgren A, et al. Increase of "-lactam-resistant invasive Haemophilus influenzae in Sweden, 1997 to 2010. Antimicrob Agents Chemother 2012; 56:4408. Topic 8048 Version 13.0

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GRAPHICS Recommended antimicrobial therapy for specific pathogens causing community-acquired pneumonia in adults
Organism
Streptococcus pneumoniae
Penicillin nonresistant; MIC <2 microgram/mL Penicillin G, amoxicillin Macrolide, cephalosporins (oral [cefpodoxime, cefprozil, cefuroxime, cefdinir, cefditoren] or parenteral [cefuroxime, ceftriaxone, cefotaxime]), clindamycin, doxycyline, respiratory fluoroquinolone* Vancomycin, linezolid, high-dose amoxicillin (3 g/day with penicillin MIC "4 microgram/mL)

Preferred antimicrobial(s)

Alternative antimicrobial(s)

Penicillin resistant; MIC !2 microgram/mL

Agents chosen on the basis of susceptibility, including cefotaxime, ceftriaxone, fluoroquinolone

Haemophilus influenzae
Non-beta-lactamase producing Beta-lactamase producing Amoxicillin Second- or third-generation cephalosporin, amoxicillinclavulanate Fluoroquinolone, doxycycline, azithromycin, clarithromycin Fluoroquinolone, doxycycline, azithromycin, clarithromycin

Mycoplasma pneumoniae/Chlamydophila pneumoniae Legionella species Chlamydophila psittaci Coxiella burnetii Francisella tularensis Yersinia pestis Bacillus anthracis (inhalation) Enterobacteriaceae

Macrolide, a tetracycline

Fluoroquinolone

Fluoroquinolone, azithromycin A tetracycline A tetracycline Doxycycline Streptomycin, gentamicin Ciprofloxacin, levofloxacin, doxycycline (usually with second agent) Third-generation cephalosporin, carbapenem # (drug of choice if extendedspectrum beta-lactamase producer)

Doxycyline Macrolide Macrolide Gentamicin, streptomycin Doxycyline, fluoroquinolone Other fluoroquinolones; beta-lactam, if susceptible; rifampin; clindamycin; chloramphenicol Beta-lactam/beta-lactamase inhibitor $, fluoroquinolone

Pseudomonas aeruginosa

Antipseudomonal beta

Aminoglycoside plus (ciprofloxacin or

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lactam plus (ciprofloxacin or levofloxacin or aminoglycoside) Burkholderia pseudomallei Acinetobacter species Staphylococcus aureus
Methicillin susceptible Methicillin resistant Antistaphylococcal penicillin Vancomycin or linezolid

levofloxacin )

Carbapenem, ceftazidime Carbapenem

Fluoroquinolone, TMP-SMX Cephalosporin-aminoglycoside, ampicillinsulbactam, colistin

Cefazolin, clindamycin TMP-SMX

Bordetella pertussis Anaerobe (aspiration)

Macrolide Beta-lactam/betalactamase inhibitor $, clindamycin See associated topic reviews Isoniazid plus rifampin plus ethambutol plus pyrazinamide For uncomplicated infection in a normal host, no therapy generally recommended; for therapy, itraconazole, fluconazole

TMP-SMX Carbapenem

Influenza virus Mycobacterium tuberculosis

Depends on susceptibility pattern. See associated topic reviews. Amphotericin B

Coccidioides species

Histoplasmosis Blastomycosis

Itraconazole** Itraconazole**

Amphotericin B** Amphotericin B**

Choices should be modified on the basis of susceptibility test results and advice from local specialists. Refer to local references for appropriate doses. Preferred agent may change over time due to changing resistance patterns and depends on many factors, including severity of illness. See associated topic reviews for updated and detailed treatment recommendations for each pathogen.
ATS: American Thoracic Society; CDC: Centers for Disease Control and Prevention; IDSA: Infectious Diseases Society of America; TMP-SMX: trimethoprim-sulfamethoxazole. * Levofloxacin, moxifloxacin, gemifloxacin (not a first-line choice for penicillin susceptible strains); ciprofloxacin is appropriate for Legionella and most gram-negative bacilli (including H. influenzae). Azithromycin is more active in vitro than clarithromycin for H. influenzae. # Imipenem-cilastatin, meropenem, ertapenem. Piperacillin-tazobactam for gram-negative bacilli, ticarcillin-clavulanate, ampicillin-sulbactam or amoxicillin-clavulanate.
$

Ticarcillin, piperacillin, ceftazidime, cefepime, aztreonam, imipenem, meropenem. 750 mg daily. Nafcillin, oxacillin, flucloxacillin.

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Choice of antiviral regimen depends on type of influenza virus and expected resistance pattern. (See "Antiviral drugs for the treatment of influenza in adults"). ** Preferred agent depends on severity of illness. See associated topic reviews for full discussions. Adapted with permission from: Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thorac Society Consensus Guidelines on the Management of Community-acquired Pneumonia in Adults. Clin Infect Dis 2007; 44:S27. Copyright 2007 University of Chicago Press. Graphic 64816 Version 5.0

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