Hemophilus Influenzae

Background

Hemophilus influezae is a common cause of bacterial infections in the pediatric population. The introduction of the Hib vaccine for children has dramatically reduced the incidence of disease.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Prognosis and Treatment

Commonly Used Terms

EPIDEMIOLOGY CHARACTERIZATION

GEOGRAPHY

BRAZIL

An Epidemiological Study of Haemophilus influenzae at a Brazilian Day Care Center.

da Silva ME, Marin JM.

University of Sao Paulo, SP, Brazil.
Braz J Infect Dis 2001 Oct;5(5):260-8 Abstract quote
Day care centers are a relatively new phenomenon in Brazil that bring together large numbers of young children susceptible to contagious diseases. Haemophilus influenzae (Hi) is an important infection in the age range of those attending day care centers.

In the present study, the carriage rate of Haemophilus influenzae was identified in 38 day care attendees age 6 to 37 months, and 23 staff members, at a day care center in Ribeirao Preto-Sao Paulo, in 1997. To identify the carriers, two nasopharyngeal swabs were collected; one in July and one in December. The rate of H. influenzae carriers among the children was 77%. Only 2 of 23 staff members (9%) had Hi. Among the children, there were 58 isolates in the two sampling periods; 6 of the Hi were serotype b, 1 was serotype e, and 48 isolates were non-typeable. Two were identified as H. parainfluenzae. One adult had a non-typeable Hi and 1 had H. paraphrohaemolyticus. Three of the 6 children with type B had received a conjugate vaccine against H. influenzae type b, but they still carried this bacterium in the nasopharynx (50%). Forty ribotype patterns were found among the isolates, showing a high exchange rate of nontypeable H. influenzae carriers.

The results indicate that, because of the high and changing biotype of Hi carriage, day care centers should be carefully monitored as potential point source of HI disease in the community.

INDIA

Are Haemophilus influenzae infections a significant problem in India? A prospective study and review.

Invasive Bacterial Infections Surveillance (IBIS) Group of the International Clinical Epidemiology Network.

All India Institute of Medical Sciences, New Delhi.

Clin Infect Dis 2002 Apr 1;34(7):949-57 Abstract quote
It has been suggested Haemophilus influenzae serotype b (Hib) disease is uncommon in Asia. During 1993--1997, we conducted prospective surveillance of acute infections caused by H. influenzae in 6 academic referral Indian hospitals.

The study included 5798 patients aged 1 month to 50 years who had diseases likely to be caused by H. influenzae; 75% of the patients were aged <5 years. A total of 125 H. influenzae infections were detected, 97% of which were caused by Hib. Of 125 isolates, 108 (86%) were from children aged <5 years, and 11 (9%) were from adults aged >18 years. Sixty-two percent of the patients had meningitis. The case-fatality rate was 11% overall and 20% in infants with Hib meningitis. Up to 60% of all isolates were resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, or erythromycin; 32% were resistant to >/= 3 antimicrobial drugs, but none were resistant to third-generation cephalosporins.

These data suggest that available Hib vaccines will benefit Indian children.

ITALY

Seasonal variations in nasopharyngeal carriage of respiratory pathogens in healthy Italian children attending day-care centres or schools.

Marchisio P, Gironi S, Esposito S, Schito GC, Mannelli S, Principi N; Ascanius Project Collaborative Group.

Pediatric Department 1, University of Milan, Italy.
J Med Microbiol 2001 Dec;50(12):1095-9 Abstract quote
The aim of this study was to investigate seasonal variations in the prevalence of the nasopharyngeal carriage of respiratory pathogens and identify factors affecting colonisation patterns in healthy children.

The nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis during two seasons (autumn and spring) was evaluated in 1580 healthy children aged 1-7 years by means of a cohort study conducted in day-care centres and schools in eight Italian cities. A questionnaire was used to obtain the epidemiological data. In all, 309 children (19.5%) carried one or more respiratory pathogens in the autumn, and 375 children (23.7%) in the spring. This variation was due to H. influenzae alone or in combination (autumn: S. pneumoniae 60, 3.8%; H. influenzae 206, 13.0%, M. catarrhalis 71, 4.5%; spring: S. pneumoniae 75, 4.7%; H. influenzae 288, 18.2%, M. catarrhalis 82, 5.2%). Colonisation with two or more pathogens increased from 9.1% in the spring to 17.3% in the autumn.

Seasonal variations occur in the prevalence of the nasopharyngeal carriage of respiratory pathogens in healthy children attending day-care centres or schools in Italy. However, although statistically significant, the difference was slight and had limited clinical relevance. Therefore, seasonal influence on the nasopharyngeal carriage of respiratory pathogens in healthy children was negligible.

LATIN AMERICA

Prevalence of beta-lactamase production in H. influenzae isolated in Latin America in 1998-1999: results of the LASER study.

Lopez-Vidal Y, Palavecino E, Rossi F.

GlaxoSmithKline, Av Insurgentes Sur 1605. Piso 20, Col San Jose Insurgentes, CP 01020, Mexico City, Mexico
Int J Antimicrob Agents 2002 Mar;19(3):201-5 Abstract quote
The objective of this study was to assess the prevalence of beta-lactamase production in Haemophilus influenzae clinical isolates obtained throughout Latin America and the West Indies in 1998-1999.

Isolates were collected from 15 centres (seven countries), identified by standard methods and grouped by patient age. The overall prevalence of beta-lactamase production was 17.8% (270/1513 isolates). The prevalence of beta-lactamase positive strains varied between countries, with the highest prevalence detected in Panama (23.4%, 29/124) and the lowest in the West Indies (10.5%, 4/38). beta-Lactamase-positive strains were more frequently isolated from children aged </=3 years (22.0%) and from adults aged >/=65 years (26.5%).

The high prevalence of beta-lactamase production found should be considered when choosing empirical antibiotic therapy where H. influenzae is suspected.

DISEASE ASSOCIATIONS CHARACTERIZATION

GENETIC FACTORS

Genetic factors in Haemophilus influenzae type b disease susceptibility and antibody acquisition.

Petersen GM, Silimperi DR, Rotter JI, Terasaki PI, Schanfield MS, Park MS, Ward JI.
J Pediatr 1987 Feb;110(2):228-33 Abstract quote
Because Alaskan Eskimos have the greatest known endemic risk of Haemophilus influenzae type b (Hib) disease and represent a comparatively homogeneous population, we selected this population to evaluate the presence or absence of an association of 35 genetic markers (alleles or allotypes) at 12 chromosomal loci with susceptibility to both invasive Hib disease risk and level of Hib anticapsular antibody.

We studied nearly all Alaskan Eskimo children who had had invasive Hib disease between 1971 and 1982 in southwestern Alaska (n = 103) and an equivalent number of controls matched for age, race, and village of residence, and verified not to have had proved or suspected Hib disease. We found no significant associations with Hib disease for the single alleles of HLA-A, -B, -C, -DR, Gm, Km, Am, Kidd, MNSs, ABO, esterase D, or glutamate pyruvate transaminase loci. However, we observed a significant interaction of two loci, Gm(a;..;g,s,t) allotype and HLA-DR8 (P = 0.002), with increased Hib disease susceptibility, and an interaction of the same Gm allotype and HLA-DR5 with decreased disease susceptibility (P = 0.01). We also compared the level of anticapsular antibody to Hib with each genetic marker and two-locus interactions, but no genetic association with antibody level was found.

We conclude that some genetic factors contribute to the susceptibility to invasive Hib disease in this population.

PATHOGENESIS CHARACTERIZATION

IgA1 PROTEASE LEVELS

Nontypeable Haemophilus influenzae in Carriage and Disease

A Difference in IgA1 Protease Activity Levels

Srdjan Vitovski, PhD; Kim T. Dunkin, BSc, MPhil, FIBMS; Anthony J. Howard, MBBS, MSc, FRCPath; Jon R. Sayers, PhD

JAMA. 2002;287:1699-1705 Abstract quote

Context
Nontypeable Haemophilus influenzae strains form part of the normal flora of the human upper respiratory tract but are also implicated in a wide range of diseases. Infections caused by nontypeable H influenzae are major health and socioeconomic burdens. No single bacterial trait has been associated with disease as opposed to colonization.

Objectives
To compare IgA1 protease activity in nontypeable H influenzae strains isolated from patients with symptomatic Haemophilus infection (sputum, cerebrospinal fluid, blood, or normally sterile tissue) vs strains from throat swabs of asymptomatic carriers and to compare iga gene carriage and variability in nontypeable H influenzae strains.

Design and Setting
Retrospective study of 63 strains (44 clinical and 19 carriage) collected between 1991 and 2000 and maintained at the Public Health Laboratory, Gwynedd General Hospital, Bangor, Wales.

Main Outcome Measures
Levels of IgA1 protease activity produced by carriage strains and clinical isolates from symptomatic patients; the determination of the size and sequence of a variable region of the iga gene.

Results
Bacterial IgA1 protease activity was significantly higher (P<.001) in strains isolated from sputum, blood, cerebrospinal fluid, or normally sterile tissue of symptomatic individuals (median, 155 mU; interquartile range [IQR], 80-220 mU; mean, 169 mU; 95% confidence interval [CI], 126-211 mU) than in those isolated from throat swabs of asymptomatic carriers (median, 30 mU; IQR, 15-90 mU; mean, 56 mU; 95% CI, 26-86 mU; assayed on secretory IgA). The iga gene was detected in 97% of all strains examined. Variations in the sizes and sequences of part of the iga genes were also apparent. This variable region encodes a polypeptide linker connecting the protease domain to the -core autotranslocator, a porelike structure required for secretion of the protease.

Conclusions
These findings reveal the importance of iga gene variability and expression levels in the establishment of disease phenotype. They identify nontypeable H influenzae IgA1 protease as a virulence factor and as a potential target for the development of new strategies to fight these important pathogens.

VARIANTS-STRAIN

Limited Genetic Diversity of Recent Invasive Isolates of Non-Serotype b Encapsulated Haemophilus influenzae.

Omikunle A, Takahashi S, Ogilvie CL, Wang Y, Rodriguez CA, St Geme JW 3rd, Adderson EE.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee. Department of Microbiology, Joshi-Eiyoh University, Saitama 350-0288, Japan. Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri.
J Clin Microbiol 2002 Apr;40(4):1264-1270 Abstract quote
Invasive infections caused by non-type b encapsulated Haemophilus influenzae have increased in frequency in the last decade. This change prompted us to characterize the genetic relationships of 48 recently isolated invasive H. influenzae type a (Hia), e (Hie), and f (Hif) strains by comparison of restriction digest patterns (RDPs). Recent Hia isolates exhibited moderate genetic diversity, with the majority segregating into two major clonotypes. Recent Hie and, especially, Hif strains displayed considerably restricted genetic diversity. In particular, all but one Hif strain segregated into a single clonotype, and half of these isolates had identical RDPs.

These results are consistent with the hypothesis that the increased incidence of disease due to non-type b encapsulated H. influenzae reflects the emergence of hypervirulent clones, especially in the case of Hif. Alternatively, it is possible that non-type b encapsulated H. influenzae strains have limited overall genetic diversity.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LABORATORY MARKERS

Use of Pulsed-Field Gel Electrophoresis, Enterobacterial Repetitive Intergenic Consensus Typing, and Automated Ribotyping To Assess Genomic Variability among Strains of Nontypeable Haemophilus influenzae.

Pettigrew MM, Foxman B, Ecevit Z, Marrs CF, Gilsdorf J.

Department of Epidemiology, University of Michigan, Ann Arbor, Michigan 48109-2029, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109-0244.
J Clin Microbiol 2002 Feb;40(2):660-2 Abstract quote
We compared 75 nontypeable (NT) Haemophilus influenzae isolates by pulsed-field gel electrophoresis (PFGE), enterobacterial repetitive intergenic consensus (ERIC)-PCR, and automated ribotyping. PFGE was the most discriminatory of the techniques.

ERIC-PCR provides a useful screen but should not replace other techniques as the sole method to group NT H. influenzae strains.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

VARIANTS

EYE

Biotypes and serotypes of Haemophilus influenzae ocular isolates.

Alrawi AM, Chern KC, Cevallos V, Lietman T, Whitcher JP, Margolis TP, Cunningham ET Jr.

The Francis I Proctor Foundation and the Department of Ophthalmology, UCSF, Medical Center, San Francisco, CA 94143, USA.
Br J Ophthalmol 2002 Mar;86(3):276-7 Abstract quote
Aim: To determine which subtypes of Haemophilus influenzae are most commonly associated with ocular disease, and whether the site of ocular H influenzae infection is correlated with specific subtypes of the organism.

Methods: The biotypes and serotypes of ocular H influenzae isolates collected at the Francis I Proctor Foundation between March 1989 and January 2000 were examined. A total of 62 ocular isolates were retrieved from frozen storage and plated on chocolate agar. Biotypes were assigned based upon the ability of the isolates to produce indole, urease, and ornithine decarboxylase. Capsular subtypes a--f were determined by slide agglutination using commercially available subtype specific antisera. Identified biotypes and serotypes were then analysed with regard to site of infection.

Results: Patient age ranged from 1 to 92 years with a median age of 45 years. 38 (61%) of the isolates were biotype II, 23 (37%) were biotype III, and one (2%) was biotype VII. All of the isolates were non-encapsulated and thus serologically non-typable. H influenzae biotype II was found in 28 of 48 (58%) conjunctivitis cases, five of eight (63%) keratitis cases, and two of two (100%) endophthalmitis cases. Biotype III was found in 20 of 48 (42%) conjunctivitis cases, two of eight (25%) keratitis cases, and a single case of dacryocystitis. Biotype VII was associated with one of eight (13%) keratitis cases.

Conclusion: Most ocular H influenzae isolates appear to be serologically non-typable strains from biotypes II and III, less virulent subtypes that frequently colonise the nasopharynx. In addition, the site of ocular H influenzae infections appears to be largely independent of species subtype.

MENINGITIS

Bacterial meningitis in childhood at the Children's Hospital of Pittsburgh: 1988-1998.

Neuman HB, Wald ER.

University of Pittsburgh School of Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, PA 15213, USA.

Clin Pediatr (Phila) 2001 Nov;40(11):595-600 Abstract quote
Bacterial meningitis is an important acute infectious disease of childhood that remains a source of substantial morbidity and mortality. The impact of the Haemophilus influenzae type b (HIB) conjugate vaccines on the epidemiology of the other bacterial causes of meningitis in childhood has received little attention.

The objective of this study is to report the experience at a tertiary-care children's hospital with the occurrence of bacterial meningitis before and after the licensure of the HIB conjugate vaccine. With use of International Classification of Diseases diagnostic codes for bacterial meningitis, a list of all children admitted to Children's Hospital of Pittsburgh with a primary or secondary diagnosis of meningitis due to H. influenzae, Streptococcus pneumoniae, and Neisseria meningitidis from January 1, 1988, to December 31, 1998, was constructed. Medical records were examined for basic patient demographic information including age, gender, race, bacterial etiology of meningitis, receipt of vaccine for HIB, underlying conditions, and fatalities.

Two hundred twenty-one cases of bacterial meningitis caused by H. influenzae, N. meningitidis, and S. pneumoniae were identified. The age of infected children ranged from 1 month to 18 years, with a mean and median age of 38.1 months and 13 months, respectively. Fifty-two percent of the children were female, 83% were Caucasian and 16% were African-American.

Before the routine use of HIB conjugate vaccine, HIB was the bacterial species responsible for the greatest proportion of cases (average of 58%/year). The absolute number of cases of bacterial meningitis attributable to HIB declined after 1991 to an average of 2.5 cases/year. The number of cases of meningitis caused by S. pneumoniae and N. meningitidis have remained relatively stable between 1988 and 1998.

The case fatality rates for children with meningitis caused by H. influenzae, S. pneumoniae, and N. meningitidis were 0.0%, 9.2%, and 7.5%, respectively. Most cases of meningitis due to HIB occurred in children who had not been immunized. Three children who received the polysaccharide vaccine developed meningitis due to HIB; there were no failures of the conjugate vaccine.

UPPER RESPIRATORY INFECTION

Frequency and distribution per species, biotypes, resistance to antibiotics and beta-lactamase production of the haemophils isolated from patients with respiratory diseases.

Mihancea N.

Cantacuzino Institute, Bucharest, Romania
Roum Arch Microbiol Immunol 1998 Apr-Jun;57(2):125-37 Abstract quote
A number of 150 samples were prelevated from respiratory tract secretions of 88 patients with respiratory infections and three healthy subjects; 162 haemophilus strains were isolated, identified and studied and the following results were obtained: H. parainfluenzae was isolated from tonsillitis and laryngitis--over 70%, bronchitis--58% and pharyngitis--56.6%; H. influenzae was isolated from pharyngitis--26.4%, bronchitis--16.1% and tonsillitis--13.6% cases; H. parahaemolyticus from bronchitis--19.3%, tonsillitis--13.6% and laryngitis. H. paraphrophilus was isolated (6.8%) from pharyngitis, tonsillitis, sinusitis, bronchitis and pulmonary abscess and H. paraphrohaemolyticus was isolated--4.5% from pharyngitis, synusitis, bronchitis and pulmonary sarcoidosis.

Most of the isolates belonged to biotype II H. influenzae and biotypes II, I, III H. parainfluenzae. Haemophils were 100% sensitive to Ofloxacin and resistant to Cro--13.5%, Do--17.9%, C and Caz--22.2%, Aml--24.6%, Rd--40.7%, Amp--41.9% and Te--63.5%; varying according to the haemophilus species. H. influenzae was resistant to Do--14.2%, Caz and C--21.4%, H. parainfluenzae was resistant to Cro--11%, Do--22%, whilst H. parahaemolyticus was resistant to Do--9% and to Aml, Caz and Cro--13.6%. Haemophils isolated from sputum showed a resistance higher by 12-34% and 6-17% than those isolated from other specimens, such as pharyngeal exudate, where the resistance to rifadin was lower by 10%. beta-lactamases were present in 27.7% of the strains: H. parainfluenzae--36%, H. paraphrohaemolyticus--25%, H. influenzae--17.8% and H. parahaemolyticus--15.7%; in strains from sputum--34.2%, pharyngeal exudate--28.8% and from other specimens--6.6%.

No correlations were noticed between the biotype and the clinical manifestation or the resistance to the antibiotic, a higher frequency of beta-lactamase production being reported in H. influenzae biotype V and H. parainfluenzae biotypes II and IV.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

BETA-LACTAMASE

Antibiotic susceptibilities of Haemophilus influenzae in central Scotland.

Shanahan PM, Thomson CJ, Amyes SG.

Scottish Antibiotic Reference Laboratory, Department of Medical Microbiology, University of Edinburgh, Edinburgh, UK.
Clin Microbiol Infect 1996 Mar;1(3):168-174 Related Articles, Books, LinkOut

Antibiotic susceptibilities of Haemophilus influenzae in central Scotland.

Shanahan PM, Thomson CJ, Amyes SG.

Scottish Antibiotic Reference Laboratory, Department of Medical Microbiology, University of Edinburgh, Edinburgh, UK.

OBJECTIVE: To ascertain the incidence of antibiotic resistance in Haemophilus influenzae in central Scotland and the beta-lactamases produced by these isolates. METHODS: A total of 213 H. influenzae isolates from four medical centers in Scotland [Aberdeen (n=58), Edinburgh (n=55), Glasgow (n=64) and Dundee (n=36)] were tested for susceptibility to a range of antimicrobials including beta-lactams, beta-lactam/beta-lactamase-inhibitor combinations, and a representative 4-quinolone, antifolate and macrolide. Susceptibility testing of the beta-lactam/beta-lactamase-inhibitor combination amoxicillin plus clavulanic acid was conducted at both 2:1 and 4:1 ratios and with clavulanic acid fixed at a concentration of 2 mg/L. Each strain was further investigated for the presence of beta-lactamase activity.

RESULTS: Although the incidence of resistance to amoxicillin was 15%, in the presence of clavulanic acid, this resistance was reduced to 4.2%, 5.6% and 4.2% with the 2:1 ratio, 4:1 ratio and 2 mg/L fixed concentration, respectively. Sixteen percent of the isolates demonstrated immediate beta-lactamase production. Isoelectric focusing showed that 77.4%, 16.1% and 6.5% of the beta-lactamase-positive strains were found to contain TEM-1, VAT-1 and both TEM-1 and VAT-1 beta-lactamases, respectively. A further 29% of the strains were recognized as being beta-lactamase-positive after prolonged incubation with nitrocephin.

CONCLUSIONS: This study suggests that current testing for beta-lactamases may underestimate the prevalence of beta-lactamase production in H. influenzae.

Haemophilus influenzae resistance in Latin America: systematic review of surveillance data.

de Andrade AL, Brandileone MC, Di Fabio JL, Oliveira RM, Silva SA, Baiocchi SS, Martelli CM.

Institute of Tropical Pathology and Public Health, Federal University of Goias, Brazil.
Microb Drug Resist 2001 Winter;7(4):403-11 Abstract quote
Haemophilus influenzae is a relevant cause of morbidity and mortality among children under 5 years of age in the developing world. In Latin America, H. influenzae type b (Hib) conjugate vaccine and surveillance of H. influenzae antimicrobial susceptibility have been implemented in recent years.

We have undertaken a systematic review and a pooled analysis on H. influenzae antimicrobial resistance, including reports of 15 Latin America countries over a 10-year period (1990-2000). We have found that 450 (21.4%) of 2,100 invasive isolates were beta-lactamase producers compared to 145 (14.5%) of 998 isolates of noninvasive isolates (p < 0.05). Ampicillin resistance was detected among 783 (21.9%) of 3,577 invasive isolates compared to 111 (17.2%) of 646 noninvasive strains (p < 0.05). In contrast, 568 (41.9%) of 1,355 noninvasive strains were trimethoprim-sulfamethoxazole (TMP-SMX) resistance against 241 (26.9%) of 897 invasive ones (p < 0.05). Therefore, TMP-SMX resistance was more common in nonsterile fluids than in sterile fluids. Over time, rates of beta-lactamase-producing strains were stable in Brazil and Mexico, whereas rates of TMP-SMX resistance were increasing in Brazil. It is predictable that following the Hib immunization, Latin America countries will be faced with increased nontypeable H. influenzae infection.

Although standing by the nontypeable H. influenzae vaccine, in this novel epidemiological scenario of post-Hib vaccination in Latin America settings there is a need to improve H. influenzae resistance monitoring to guide clinicians to choose efficacious antimicrobial therapy.

Apparent plateau in beta-lactamase production among clinical isolates of Haemophilus influenzae and Moraxella catarrhalis in the United States: results from the LIBRA Surveillance initiative.

Jones ME, Karlowsky JA, Blosser-Middleton R, Critchley IA, Thornsberry C, Sahm DF.

Focus Technologies, Koninginneweg 11, 1217 KP, Hilversum, The Netherlands.
Int J Antimicrob Agents 2002 Feb;19(2):119-23 Abstract quote
Haemophilus influenzae (n=2791) and Moraxella catarrhalis (n=1249) isolated from patient specimens during 1999 were collected from 290 laboratories participating in a moxifloxacin surveillance study as part of the LIBRA Surveillance initiative.

Isolates were tested for in vitro susceptibility to a panel of agents suitable for the treatment of respiratory tract infections. beta-Lactamase production was identified in 32.2% of H. influenzae and 94.2% of M. catarrhalis. These percentages differed by less than 1.5% from results of a study conducted in 1997-1998 and were similar to results from other recent US surveillance studies. Resistance among H. influenzae to trimethoprim-sulphamethoxazole increased considerably, from 2% in the 1997-1998 study (n=6588 H. influenzae) to 15.5% in the current study. One isolate of H. influenzae had an MIC of 8 mg/l to both levofloxacin and moxifloxacin; all other isolates had MICs of < or =0.5 mg/l and < or =0.25 mg/l, respectively. beta-Lactamase production was found to confer ampicillin resistance in nearly all isolates. For M. catarrhalis, beta-lactamase-negative isolates had MICs < or =0.12-0.25 mg/l for ampicillin and < or =0.03-0.12 mg/l for ceftriaxone. In contrast, beta-lactamase production resulted in MICs of < or = 0.12->16 mg/l for ampicillin and < or = 0.03-4 mg/l for ceftriaxone. All M. catarrhalis had MICs < or =0.12 mg/l for moxifloxacin and < or =1 mg/l for levofloxacin.

In summary, antimicrobial susceptibilities and the prevalence of beta-lactamase production in H. influenzae and M. catarrhalis in the United States has remained essentially unchanged from 1997-1998 to 1999.

TREATMENT

ANTIBIOTICS

Activity of cefditoren against beta-lactamase-positive and -negative Haemophilus influenzae and Moraxella catarrhalis.

Karlowsky JA, Critchley IA, Draghi DC, Jones ME, Thornsberry C, Sahm DF.

Focus Technologies, Inc., 13665 Dulles Technology Drive, Herndon, Virginia 20171, USA
Diagn Microbiol Infect Dis 2002 Jan;42(1):53-8 Abstract quote
Cefditoren is a novel broad-spectrum oral cephalosporin.

To determine the influence of beta-lactamase production on cefditoren activity, 1,170 H. influenzae and 641 M. catarrhalis isolated during 2000 were tested by NCCLS broth microdilution methodology (M7-A5, 2000). Against H. influenzae the potency of cefditoren (MIC(90,) 0.015 microg/mL) was similar to that of ceftriaxone (MIC(90,) < or = 0.015 microg/mL) and levofloxacin (MIC(90,) 0.015 microg/mL), and its MIC distribution was unaffected by beta-lactamase production. In comparison, the beta-lactamase status of M. catarrhalis affected the potency of all beta-lactams tested, including cefditoren, as well as trimethoprim-sulfamethoxazole. However, regardless of the presence of beta-lactamase, cefditoren demonstrated potent activity, as concentrations of 0.5 and 1 microg/mL inhibited 93.1 and 100% of M. catarrhalis isolates, respectively.

We conclude that cefditoren is highly active in vitro against beta-lactamase-positive H. influenzae and M. catarrhalis

Comparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999-2000.

Koeth LM, Jacobs MR, Bajaksouzian S, Zilles A, Lin G, Appelbaum PC.

Laboratory Specialists, Inc., 1651 A Crossings Parkway, Westlake, OH 44145, USA.
Int J Antimicrob Agents 2002 Jan;19(1):33-7 Abstract quote
This study was undertaken to assess the in vitro activity of gemifloxacin, five other fluoroquinolone antimicrobial agents (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin and ofloxacin) and other non-quinolone comparator agents (ampicillin, erythromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulphamethoxazole) against Streptococcus pneumoniae collected in the United States.

Susceptibility testing of 550 S. pneumoniae, 290 Haemophilus influenzae and 205 Moraxella catarrhalis showed that 38.2% of pneumococci were penicillin nonsusceptible, while 26.2 and 95.6% of H. influenzae and M. catarrhalis, respectively, produced beta-lactamase. Overall new fluoroquinolones were the most active agents.

The in vitro activity (based on MIC90 in mg/l) of the six fluoroquinolones was gemifloxacin>moxifloxacin>gatifloxacin>levofloxacin>ciprofloxacin and ofloxacin.

Antimicrobial resistance trends in community-acquired respiratory tract pathogens in the Western Pacific Region and South Africa: report from the SENTRY antimicrobial surveillance program, (1998-1999) including an in vitro evaluation of BMS284756.

Bell JM, Turnidge JD, Jones RN; The SENTRY Regional Participants Group.,Adelaide, Australia
Int J Antimicrob Agents 2002 Feb;19(2):125-32 Abstract quote
From 1998 to 1999, a large number of community-acquired respiratory tract isolates of Streptococcus pneumoniae (n=566), Haemophilus influenzae (n=513) and Moraxella catarrhalis (n=228) were collected from 15 centres in Australia, Hong Kong, Japan, China, the Philippines, Singapore, South Africa and Taiwan through the SENTRY Antimicrobial Surveillance Program.

Isolates were tested against 26 antimicrobial agents using the NCCLS-recommended methods. Overall, 40% of S. pneumoniae isolates were resistant to penicillin with 18% of strains having high-level resistance (MIC > or =2 mg/l). Rates of erythromycin and clindamycin resistance were 41 and 23%, respectively. Penicillin-resistant strains showed high rates of resistance to other antimicrobial agents: 96% to trimethoprim-sulphamethoxazole (TMP-SMX), 84% to tetracycline and 81% to erythromycin. A significant proportion of penicillin-susceptible strains was also resistant to erythromycin (21%), tetracycline (29%) and TMP-SMZ (26%). Small numbers of strains were resistant to levofloxacin (0.7%), trovafloxacin (0.4%) and grepafloxacin (1.3%) where as all strains remained uniformly susceptible to quinupristin/dalfopristin and BMS284756 (MIC(90), 0.06 mg/l), a new desfluoroquinolone. beta-lactamases were, produced by 20% H. influenzae isolates and only rare strains showed intrinsic resistance to amoxycillin. Other beta-lactam agents showed good activity with rates of resistance less than 2% and all isolates showed susceptibility to cefixime, ceftibuten, cefepime and cefotaxime. Rates of resistance to tetracycline and chloramphenicol were also relatively low at 3%.

The majority (98%) of M. catarrhalis isolates was fouClin Infect Dis 2002 Mar 1;34 Suppl 1:S4-S16 Related Articles, Books, LinkOut

Comment in:
Clin Infect Dis. 2002 Mar 1;34 Suppl 1:S1-3.

Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999-2000.

Thornsberry C, Sahm DF, Kelly LJ, Critchley IA, Jones ME, Evangelista AT, Karlowsky JA.

Focus Technologies Inc., Nashville, TN, USA. jkarlowsky@focus answers.com

The ongoing TRUST (Tracking Resistance in the United States Today) study, which began monitoring antimicrobial resistance among respiratory pathogens in 1996, routinely tracks resistance at national and regional levels. The 1999-2000 TRUST study analyzed 9499 Streptococcus pneumoniae, 1934 Haemophilus influenzae, and 1108 Moraxella catarrhalis isolates that were prospectively collected from 239 laboratories across the 9 US Bureau of the Census regions. Penicillin-resistant S. pneumoniae varied significantly by region, from 8.3% to 24.8% (P<.001). In each region, penicillin resistance closely predicted resistance to other beta-lactams, macrolides, and trimethoprim-sulfamethoxazole. Levofloxacin resistance was 0.5% nationally (regional range, 0.1%-1.0%). Multidrug resistance also varied significantly (P<.001) by region. beta-Lactamase production among H. influenzae varied significantly (regional range, 24.0%-34.6%) and M. catarrhalis (86.2%-96.8%) also varied by region. Notable variation in regional antimicrobial resistance rates (S. pneumoniae) and beta-lactamase production (H. influenzae, M. catarrhalis) exists throughout the United States.

nd to be beta-lactamase-positive and resistant to penicillins, however, resistance to erythromycin and tetracycline was also low at 1.8%. Both H. influenzae and M. catarrhalis isolates were uniformly susceptible to the new desfluoroquinolone and tested fluoroquinolones

Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999-2000.

Thornsberry C, Sahm DF, Kelly LJ, Critchley IA, Jones ME, Evangelista AT, Karlowsky JA.

Focus Technologies Inc., Nashville, TN, USA.
Clin Infect Dis 2002 Mar 1;34 Suppl 1:S4-S16 Abstract quote
The ongoing TRUST (Tracking Resistance in the United States Today) study, which began monitoring antimicrobial resistance among respiratory pathogens in 1996, routinely tracks resistance at national and regional levels.

The 1999-2000 TRUST study analyzed 9499 Streptococcus pneumoniae, 1934 Haemophilus influenzae, and 1108 Moraxella catarrhalis isolates that were prospectively collected from 239 laboratories across the 9 US Bureau of the Census regions. Penicillin-resistant S. pneumoniae varied significantly by region, from 8.3% to 24.8% (P<.001). In each region, penicillin resistance closely predicted resistance to other beta-lactams, macrolides, and trimethoprim-sulfamethoxazole. Levofloxacin resistance was 0.5% nationally (regional range, 0.1%-1.0%).

Multidrug resistance also varied significantly (P<.001) by region. beta-Lactamase production among H. influenzae varied significantly (regional range, 24.0%-34.6%) and M. catarrhalis (86.2%-96.8%) also varied by region. Notable variation in regional antimicrobial resistance rates (S. pneumoniae) and beta-lactamase production (H. influenzae, M. catarrhalis) exists throughout the United States.

VACCINE

Progress toward elimination of Haemophilus influenzae type b disease among infants and children--United States, 1993-1994
MMWR Morb Mortal Wkly Rep 1995 Jul 28;44(29):545-50 Abstract quote
Before effective vaccines were available, Haemophilus influenzae type b (Hib) was the most common cause of bacterial meningitis among children in the United States. Since the introduction of Hib conjugate vaccines in 1988, the incidence of invasive Hib infection has declined by at least 95% among infants and children (1,2).

As part of the Childhood Immunization Initiative (CII), the Public Health Service has included Hib disease among children aged < 5 years as one of the vaccine-preventable diseases targeted for elimination in the United States by 1996 (3).

This report summarizes provisional data about invasive Hi disease during 1993-1994 based on information from three surveillance systems: the National Notifiable Diseases Surveillance System (NNDSS), the National Bacterial Meningitis and Bacteremia Reporting System (NBMBRS), and a multistate laboratory-based surveillance system.

Clinical and immunological risk factors associated with Haemophilus influenzae type b conjugate vaccine failure in childhood.

Heath PT, Booy R, Griffiths H, Clutterbuck E, Azzopardi HJ, Slack MP, Fogarty J, Moloney AC, Moxon ER.

Oxford Vaccine Group, John Radcliffe Hospital, Oxford, United Kingdom.
Clin Infect Dis 2000 Oct;31(4):973-80 Abstract quote
Haemophilus influenzae type b (Hib) conjugate vaccines have proved extremely efficacious in healthy children. True Hib vaccine failures are rare. Hib conjugate vaccines were introduced for routine immunization in the United Kingdom and the Republic of Ireland in 1992. Coincident with this, active prospective and national surveillance via pediatricians, microbiologists, and public health physicians was commenced to assess the clinical and immunological factors associated with vaccine failure.

During the 6 years of the study, 115 children with true vaccine failure were reported. Of the children who were vaccinated before 12 months of age, a clinical risk factor was detected in 20%, an immunological deficiency was detected in 30%, and one or both were detected in 44%. Children who were vaccinated after 12 months of age were more likely to have one or both factors (67%). Thirty percent (33 of 105) of children with true vaccine failure had a low Hib antibody response (concentration, <1.0 microg/mL) after disease, but the majority then responded to a further dose of Hib vaccine.

Children who develop Hib disease despite vaccination deserve further clinical and immunological evaluation.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Commonly Used Terms

Bacteria

Last Updated 4/4/2002

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EPIDEMIOLOGY	CHARACTERIZATION
GEOGRAPHY
BRAZIL
An Epidemiological Study of Haemophilus influenzae at a Brazilian Day Care Center. da Silva ME, Marin JM. University of Sao Paulo, SP, Brazil.	Braz J Infect Dis 2001 Oct;5(5):260-8 Abstract quote Day care centers are a relatively new phenomenon in Brazil that bring together large numbers of young children susceptible to contagious diseases. Haemophilus influenzae (Hi) is an important infection in the age range of those attending day care centers. In the present study, the carriage rate of Haemophilus influenzae was identified in 38 day care attendees age 6 to 37 months, and 23 staff members, at a day care center in Ribeirao Preto-Sao Paulo, in 1997. To identify the carriers, two nasopharyngeal swabs were collected; one in July and one in December. The rate of H. influenzae carriers among the children was 77%. Only 2 of 23 staff members (9%) had Hi. Among the children, there were 58 isolates in the two sampling periods; 6 of the Hi were serotype b, 1 was serotype e, and 48 isolates were non-typeable. Two were identified as H. parainfluenzae. One adult had a non-typeable Hi and 1 had H. paraphrohaemolyticus. Three of the 6 children with type B had received a conjugate vaccine against H. influenzae type b, but they still carried this bacterium in the nasopharynx (50%). Forty ribotype patterns were found among the isolates, showing a high exchange rate of nontypeable H. influenzae carriers. The results indicate that, because of the high and changing biotype of Hi carriage, day care centers should be carefully monitored as potential point source of HI disease in the community.
INDIA
Are Haemophilus influenzae infections a significant problem in India? A prospective study and review. Invasive Bacterial Infections Surveillance (IBIS) Group of the International Clinical Epidemiology Network. All India Institute of Medical Sciences, New Delhi.	Clin Infect Dis 2002 Apr 1;34(7):949-57 Abstract quote It has been suggested Haemophilus influenzae serotype b (Hib) disease is uncommon in Asia. During 1993--1997, we conducted prospective surveillance of acute infections caused by H. influenzae in 6 academic referral Indian hospitals. The study included 5798 patients aged 1 month to 50 years who had diseases likely to be caused by H. influenzae; 75% of the patients were aged <5 years. A total of 125 H. influenzae infections were detected, 97% of which were caused by Hib. Of 125 isolates, 108 (86%) were from children aged <5 years, and 11 (9%) were from adults aged >18 years. Sixty-two percent of the patients had meningitis. The case-fatality rate was 11% overall and 20% in infants with Hib meningitis. Up to 60% of all isolates were resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, or erythromycin; 32% were resistant to >/= 3 antimicrobial drugs, but none were resistant to third-generation cephalosporins. These data suggest that available Hib vaccines will benefit Indian children.
ITALY
Seasonal variations in nasopharyngeal carriage of respiratory pathogens in healthy Italian children attending day-care centres or schools. Marchisio P, Gironi S, Esposito S, Schito GC, Mannelli S, Principi N; Ascanius Project Collaborative Group. Pediatric Department 1, University of Milan, Italy.	J Med Microbiol 2001 Dec;50(12):1095-9 Abstract quote The aim of this study was to investigate seasonal variations in the prevalence of the nasopharyngeal carriage of respiratory pathogens and identify factors affecting colonisation patterns in healthy children. The nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis during two seasons (autumn and spring) was evaluated in 1580 healthy children aged 1-7 years by means of a cohort study conducted in day-care centres and schools in eight Italian cities. A questionnaire was used to obtain the epidemiological data. In all, 309 children (19.5%) carried one or more respiratory pathogens in the autumn, and 375 children (23.7%) in the spring. This variation was due to H. influenzae alone or in combination (autumn: S. pneumoniae 60, 3.8%; H. influenzae 206, 13.0%, M. catarrhalis 71, 4.5%; spring: S. pneumoniae 75, 4.7%; H. influenzae 288, 18.2%, M. catarrhalis 82, 5.2%). Colonisation with two or more pathogens increased from 9.1% in the spring to 17.3% in the autumn. Seasonal variations occur in the prevalence of the nasopharyngeal carriage of respiratory pathogens in healthy children attending day-care centres or schools in Italy. However, although statistically significant, the difference was slight and had limited clinical relevance. Therefore, seasonal influence on the nasopharyngeal carriage of respiratory pathogens in healthy children was negligible.
LATIN AMERICA
Prevalence of beta-lactamase production in H. influenzae isolated in Latin America in 1998-1999: results of the LASER study. Lopez-Vidal Y, Palavecino E, Rossi F. GlaxoSmithKline, Av Insurgentes Sur 1605. Piso 20, Col San Jose Insurgentes, CP 01020, Mexico City, Mexico	Int J Antimicrob Agents 2002 Mar;19(3):201-5 Abstract quote The objective of this study was to assess the prevalence of beta-lactamase production in Haemophilus influenzae clinical isolates obtained throughout Latin America and the West Indies in 1998-1999. Isolates were collected from 15 centres (seven countries), identified by standard methods and grouped by patient age. The overall prevalence of beta-lactamase production was 17.8% (270/1513 isolates). The prevalence of beta-lactamase positive strains varied between countries, with the highest prevalence detected in Panama (23.4%, 29/124) and the lowest in the West Indies (10.5%, 4/38). beta-Lactamase-positive strains were more frequently isolated from children aged </=3 years (22.0%) and from adults aged >/=65 years (26.5%). The high prevalence of beta-lactamase production found should be considered when choosing empirical antibiotic therapy where H. influenzae is suspected.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
EYE
Biotypes and serotypes of Haemophilus influenzae ocular isolates. Alrawi AM, Chern KC, Cevallos V, Lietman T, Whitcher JP, Margolis TP, Cunningham ET Jr. The Francis I Proctor Foundation and the Department of Ophthalmology, UCSF, Medical Center, San Francisco, CA 94143, USA.	Br J Ophthalmol 2002 Mar;86(3):276-7 Abstract quote Aim: To determine which subtypes of Haemophilus influenzae are most commonly associated with ocular disease, and whether the site of ocular H influenzae infection is correlated with specific subtypes of the organism. Methods: The biotypes and serotypes of ocular H influenzae isolates collected at the Francis I Proctor Foundation between March 1989 and January 2000 were examined. A total of 62 ocular isolates were retrieved from frozen storage and plated on chocolate agar. Biotypes were assigned based upon the ability of the isolates to produce indole, urease, and ornithine decarboxylase. Capsular subtypes a--f were determined by slide agglutination using commercially available subtype specific antisera. Identified biotypes and serotypes were then analysed with regard to site of infection. Results: Patient age ranged from 1 to 92 years with a median age of 45 years. 38 (61%) of the isolates were biotype II, 23 (37%) were biotype III, and one (2%) was biotype VII. All of the isolates were non-encapsulated and thus serologically non-typable. H influenzae biotype II was found in 28 of 48 (58%) conjunctivitis cases, five of eight (63%) keratitis cases, and two of two (100%) endophthalmitis cases. Biotype III was found in 20 of 48 (42%) conjunctivitis cases, two of eight (25%) keratitis cases, and a single case of dacryocystitis. Biotype VII was associated with one of eight (13%) keratitis cases. Conclusion: Most ocular H influenzae isolates appear to be serologically non-typable strains from biotypes II and III, less virulent subtypes that frequently colonise the nasopharynx. In addition, the site of ocular H influenzae infections appears to be largely independent of species subtype.
MENINGITIS
Bacterial meningitis in childhood at the Children's Hospital of Pittsburgh: 1988-1998. Neuman HB, Wald ER. University of Pittsburgh School of Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, PA 15213, USA.	Clin Pediatr (Phila) 2001 Nov;40(11):595-600 Abstract quote Bacterial meningitis is an important acute infectious disease of childhood that remains a source of substantial morbidity and mortality. The impact of the Haemophilus influenzae type b (HIB) conjugate vaccines on the epidemiology of the other bacterial causes of meningitis in childhood has received little attention. The objective of this study is to report the experience at a tertiary-care children's hospital with the occurrence of bacterial meningitis before and after the licensure of the HIB conjugate vaccine. With use of International Classification of Diseases diagnostic codes for bacterial meningitis, a list of all children admitted to Children's Hospital of Pittsburgh with a primary or secondary diagnosis of meningitis due to H. influenzae, Streptococcus pneumoniae, and Neisseria meningitidis from January 1, 1988, to December 31, 1998, was constructed. Medical records were examined for basic patient demographic information including age, gender, race, bacterial etiology of meningitis, receipt of vaccine for HIB, underlying conditions, and fatalities. Two hundred twenty-one cases of bacterial meningitis caused by H. influenzae, N. meningitidis, and S. pneumoniae were identified. The age of infected children ranged from 1 month to 18 years, with a mean and median age of 38.1 months and 13 months, respectively. Fifty-two percent of the children were female, 83% were Caucasian and 16% were African-American. Before the routine use of HIB conjugate vaccine, HIB was the bacterial species responsible for the greatest proportion of cases (average of 58%/year). The absolute number of cases of bacterial meningitis attributable to HIB declined after 1991 to an average of 2.5 cases/year. The number of cases of meningitis caused by S. pneumoniae and N. meningitidis have remained relatively stable between 1988 and 1998. The case fatality rates for children with meningitis caused by H. influenzae, S. pneumoniae, and N. meningitidis were 0.0%, 9.2%, and 7.5%, respectively. Most cases of meningitis due to HIB occurred in children who had not been immunized. Three children who received the polysaccharide vaccine developed meningitis due to HIB; there were no failures of the conjugate vaccine.
UPPER RESPIRATORY INFECTION
Frequency and distribution per species, biotypes, resistance to antibiotics and beta-lactamase production of the haemophils isolated from patients with respiratory diseases. Mihancea N. Cantacuzino Institute, Bucharest, Romania	Roum Arch Microbiol Immunol 1998 Apr-Jun;57(2):125-37 Abstract quote A number of 150 samples were prelevated from respiratory tract secretions of 88 patients with respiratory infections and three healthy subjects; 162 haemophilus strains were isolated, identified and studied and the following results were obtained: H. parainfluenzae was isolated from tonsillitis and laryngitis--over 70%, bronchitis--58% and pharyngitis--56.6%; H. influenzae was isolated from pharyngitis--26.4%, bronchitis--16.1% and tonsillitis--13.6% cases; H. parahaemolyticus from bronchitis--19.3%, tonsillitis--13.6% and laryngitis. H. paraphrophilus was isolated (6.8%) from pharyngitis, tonsillitis, sinusitis, bronchitis and pulmonary abscess and H. paraphrohaemolyticus was isolated--4.5% from pharyngitis, synusitis, bronchitis and pulmonary sarcoidosis. Most of the isolates belonged to biotype II H. influenzae and biotypes II, I, III H. parainfluenzae. Haemophils were 100% sensitive to Ofloxacin and resistant to Cro--13.5%, Do--17.9%, C and Caz--22.2%, Aml--24.6%, Rd--40.7%, Amp--41.9% and Te--63.5%; varying according to the haemophilus species. H. influenzae was resistant to Do--14.2%, Caz and C--21.4%, H. parainfluenzae was resistant to Cro--11%, Do--22%, whilst H. parahaemolyticus was resistant to Do--9% and to Aml, Caz and Cro--13.6%. Haemophils isolated from sputum showed a resistance higher by 12-34% and 6-17% than those isolated from other specimens, such as pharyngeal exudate, where the resistance to rifadin was lower by 10%. beta-lactamases were present in 27.7% of the strains: H. parainfluenzae--36%, H. paraphrohaemolyticus--25%, H. influenzae--17.8% and H. parahaemolyticus--15.7%; in strains from sputum--34.2%, pharyngeal exudate--28.8% and from other specimens--6.6%. No correlations were noticed between the biotype and the clinical manifestation or the resistance to the antibiotic, a higher frequency of beta-lactamase production being reported in H. influenzae biotype V and H. parainfluenzae biotypes II and IV.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Prognosis and Treatment
Commonly Used Terms

PATHOGENESIS	CHARACTERIZATION
IgA1 PROTEASE LEVELS
Nontypeable Haemophilus influenzae in Carriage and Disease A Difference in IgA1 Protease Activity Levels Srdjan Vitovski, PhD; Kim T. Dunkin, BSc, MPhil, FIBMS; Anthony J. Howard, MBBS, MSc, FRCPath; Jon R. Sayers, PhD	JAMA. 2002;287:1699-1705 Abstract quote Context Nontypeable Haemophilus influenzae strains form part of the normal flora of the human upper respiratory tract but are also implicated in a wide range of diseases. Infections caused by nontypeable H influenzae are major health and socioeconomic burdens. No single bacterial trait has been associated with disease as opposed to colonization. Objectives To compare IgA1 protease activity in nontypeable H influenzae strains isolated from patients with symptomatic Haemophilus infection (sputum, cerebrospinal fluid, blood, or normally sterile tissue) vs strains from throat swabs of asymptomatic carriers and to compare iga gene carriage and variability in nontypeable H influenzae strains. Design and Setting Retrospective study of 63 strains (44 clinical and 19 carriage) collected between 1991 and 2000 and maintained at the Public Health Laboratory, Gwynedd General Hospital, Bangor, Wales. Main Outcome Measures Levels of IgA1 protease activity produced by carriage strains and clinical isolates from symptomatic patients; the determination of the size and sequence of a variable region of the iga gene. Results Bacterial IgA1 protease activity was significantly higher (P<.001) in strains isolated from sputum, blood, cerebrospinal fluid, or normally sterile tissue of symptomatic individuals (median, 155 mU; interquartile range [IQR], 80-220 mU; mean, 169 mU; 95% confidence interval [CI], 126-211 mU) than in those isolated from throat swabs of asymptomatic carriers (median, 30 mU; IQR, 15-90 mU; mean, 56 mU; 95% CI, 26-86 mU; assayed on secretory IgA). The iga gene was detected in 97% of all strains examined. Variations in the sizes and sequences of part of the iga genes were also apparent. This variable region encodes a polypeptide linker connecting the protease domain to the -core autotranslocator, a porelike structure required for secretion of the protease. Conclusions These findings reveal the importance of iga gene variability and expression levels in the establishment of disease phenotype. They identify nontypeable H influenzae IgA1 protease as a virulence factor and as a potential target for the development of new strategies to fight these important pathogens.
VARIANTS-STRAIN
Limited Genetic Diversity of Recent Invasive Isolates of Non-Serotype b Encapsulated Haemophilus influenzae. Omikunle A, Takahashi S, Ogilvie CL, Wang Y, Rodriguez CA, St Geme JW 3rd, Adderson EE. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee. Department of Microbiology, Joshi-Eiyoh University, Saitama 350-0288, Japan. Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri.	J Clin Microbiol 2002 Apr;40(4):1264-1270 Abstract quote Invasive infections caused by non-type b encapsulated Haemophilus influenzae have increased in frequency in the last decade. This change prompted us to characterize the genetic relationships of 48 recently isolated invasive H. influenzae type a (Hia), e (Hie), and f (Hif) strains by comparison of restriction digest patterns (RDPs). Recent Hia isolates exhibited moderate genetic diversity, with the majority segregating into two major clonotypes. Recent Hie and, especially, Hif strains displayed considerably restricted genetic diversity. In particular, all but one Hif strain segregated into a single clonotype, and half of these isolates had identical RDPs. These results are consistent with the hypothesis that the increased incidence of disease due to non-type b encapsulated H. influenzae reflects the emergence of hypervirulent clones, especially in the case of Hif. Alternatively, it is possible that non-type b encapsulated H. influenzae strains have limited overall genetic diversity.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
Use of Pulsed-Field Gel Electrophoresis, Enterobacterial Repetitive Intergenic Consensus Typing, and Automated Ribotyping To Assess Genomic Variability among Strains of Nontypeable Haemophilus influenzae. Pettigrew MM, Foxman B, Ecevit Z, Marrs CF, Gilsdorf J. Department of Epidemiology, University of Michigan, Ann Arbor, Michigan 48109-2029, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109-0244.	J Clin Microbiol 2002 Feb;40(2):660-2 Abstract quote We compared 75 nontypeable (NT) Haemophilus influenzae isolates by pulsed-field gel electrophoresis (PFGE), enterobacterial repetitive intergenic consensus (ERIC)-PCR, and automated ribotyping. PFGE was the most discriminatory of the techniques. ERIC-PCR provides a useful screen but should not replace other techniques as the sole method to group NT H. influenzae strains.