Many controversies still remain in the management of hospital acquired pneumonia (HAP), and ventilation-acquired pneumonia (VAP), Three European Societies, European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Society of Intensive Care Medicine (ESICM), were interested in producing a document on HAP and VAP with European perspective. The scientific committees from each Society designated one chairman; Antoni Torres (ERS), Harmut Lode (ESCMID) and Jean Carlet (ESICM). The chairmen of this Task Force suggested names from each Society to be a member of the panel. They also choose controversial topics on the field and others that were not covered by the last IDSA/ATS guidelines. Each topic was assigned to a pair of members to be reviewed and written. Finally, the panel defined 20 consensual points that were circulated several times among the members of the panel until total agreement was reached. A combination of evidences and clinical-based medicine was used to reach these consensus. This manuscript reviews in depth several controversial or new topics in HAP and VAP. In addition 20 consensual points are presented. This manuscript may be useful for the development of future guidelines and to stimulate clinical research by lying out what is currently accepted and what is unknown or controversial.

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Defining, treating and preventing hospital acquired pneumonia: European perspective.

Purpose of review This review will consider recent developments in the clinical aspects of infections due to non-typeable Haemophilus influenzae. In addition, newer developments in the areas of mechanisms of pathogenesis, host pathogen interaction, immune responses and efforts toward vaccine development will be reviewed briefly. Recent findings Non-typeable H. influenzae continues to be a common cause of otitis media in infants and children, sinusitis in children and adults, pneumonia in adults, and lower respiratory tract infection in adults with chronic obstructive pulmonary disease. While the rate of beta-lactamase production by isolates of H. influenzae varies geographically, most regions show a rate of 20-35% of isolates producing beta-lactamase. Recent studies have highlighted the possible role of bacterial biofilms formed by H. influenzae as a cause of otitis media. Several lines of evidence indicate that H. influenzae causes intracellular infection in the lower respiratory tract in chronic obstructive pulmonary disease and this observation has important implications in understanding the human immune response to the bacterium. Lipooligosaccharide is an important virulence factor for H. influenzae and research is generating new information on the complex role of this molecule in colonization and infection of the respiratory tract. Several surface molecules are under active evaluation as vaccine antigens. Summary Non-typeable H. influenzae is an important cause of respiratory tract infections in children and adults. Most strains are susceptible to amoxicillin/clavulanate, fluoroquinolones and the newer macrolides. Research in the next decade promises substantial progress in the challenge of developing vaccines for nontypeable H. influenzae.

Respiratory infections caused by non-typeable Haemophilus influenzae.

A multicenter susceptibility surveillance (the S.A.U.C.E. project) including 2,721 Streptococcus pneumoniae, 3,174 Streptococcus pyogenes, and 2,645 Haemophilus influenzae consecutive isolates was carried out in 25 hospitals all over Spain from November 2001 to October 2002 to evaluate the current epidemiology of resistance of the main bacteria involved in community-acquired respiratory tract infections. Susceptibility testing was performed in a single centralized laboratory by a broth microdilution method. The prevalence of resistant S. pneumoniae strains was 0.4% for cefotaxime, 4.4% for amoxicillin and amoxicillin-clavulanic acid, 25.6% for cefuroxime-axetil, 34.5% for erythromycin, clarithromycin, and azithromycin, and 36.0% for cefaclor. Phenotypes of resistance to erythromycin were MLS(B) (macrolide-lincosamide-streptogramin B) in 89.9% (gene ermB) and M (macrolide) in 9.7% of cases (gene mefA). No strain harbored both genes simultaneously. Serotypes 19, 6, 23, 14, and 3 were the most prevalent, accounting for 54.6% of the total isolates. Resistance to macrolides seems to be the most alarming point, since among penicillin-susceptible isolates it reached 15.1% compared to 55.8% among penicillin-resistant strains. Geographically, a number of regions had rates of erythromycin resistance above 40% (even higher in children). Resistance to erythromycin was also high in S. pyogenes isolates: mean regional 33.2%, beta-lactamase-producing H. influenzae were 20%, whereas 4.4% had a beta-lactamase-negative, ampicillin-resistant phenotype. We highlight the importance of different geographical frequencies of coresistance (associations of resistance to different drugs within the same species) and coupled resistance (association of resistance between different species) probably resulting from different local coselective events.

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Geographical and Ecological Analysis of Resistance, Coresistance, and Coupled Resistance to Antimicrobials in Respiratory Pathogenic Bacteria in Spain

Little clinical and microbiological information is available about invasive Haemophilus influenzae infection after widespread vaccination against H. influenzae type b (Hib). We conducted an active community surveillance study on invasive H. influenzae during a 2-year period in a community of more than 5 million people after vaccination against Hib in children was introduced. The median incidence was 16.3 cases/100000 persons per year in children less than 1-year-old and 4.41 cases/100000 persons in children less than <5 years old. The highest incidence in adults was observed in patients greater than 70 years old. Clinical diagnoses included bacteremia, pneumonia, and meningitis. Of the H. influenzae-infected patients, 74.3% had underlying predisposing conditions, including impaired immunity and respiratory diseases. A total of 73.6% of the isolates were nontypeable and 16.5, 6.6, and 3.3% were types b, f, and e, respectively. Infections due to capsulated strains b, e, and f were evenly distributed between children and adults. Ampicillin and cotrimoxazole resistance occurred at frequencies of 24.2 and 48.4%, respectively. Antibiotic resistance was more prevalent in capsulated than in noncapsulated H. influenzae. Invasive isolates were highly resistant to antibiotics that were used infrequently in the community. Nontypeable H. influenzae were genetically much more heterogeneous than capsulated strains. Capsule-deficient mutants (b(-)) were not detected. Plasmid carriage was linked to antibiotic resistance and capsulated strains. Over the study period, the incidence of invasive H. influenzae infections, either encapsulated or not, did not increase. In the post-Hib vaccination era, most invasive infections were due to noncapsulated strains and occurred in the extreme ages of life in patients with predisposing conditions.

Analysis of Invasive Haemophilus influenzae Infections after Extensive Vaccination against H. influenzae Type b

The sequence of the ftsI gene encoding the transpeptidase domain of penicillin-binding protein 3 (PBP 3) was determined for 354 nonconsecutive Haemophilus influenzae isolates from Spain; 17.8% of them were ampicillin susceptible, 56% were beta-lactamase nonproducing ampicillin resistant (BLNAR), 15.8% were beta-lactamase producers and ampicillin resistant, and 10.4% displayed both resistance mechanisms. The ftsI gene sequences had 28 different mutation patterns and amino acid substitutions at 23 positions. Some 93.2% of the BLNAR strains had amino acid substitutions at the Lys-Thr-Gly (KTG) motif, the two most common being Asn526 to Lys (83.9%) and Arg517 to His (9.3%). Amino acid substitutions at positions 377, 385, and 389, which conferred cefotaxime and cefixime MICs 10 to 60 times higher than those of susceptible strains, were found for the first time in Europe. In 72 isolates for which the repressor acrR gene of the AcrAB efflux pump was sequenced, numerous amino acid substitutions were found. Eight isolates with ampicillin MICs of 0.25 to 2 microg/ml showed changes that predicted the early termination of the acrR reading frame. Pulsed-field gel electrophoresis analysis demonstrated that most BLNAR strains were genetically diverse, although clonal dissemination was detected in a group of isolates presenting with increased resistance to cefotaxime and cefixime. Background antibiotic use at the community level revealed a marked trend toward increased amoxicillin-clavulanic acid consumption. BLNAR H. influenzae strains have arisen by vertical and horizontal spread and have evolved to adapt rapidly to the increased selective pressures posed by the use of oral penicillins and cephalosporins.

Ampicillin-Resistant Non-β-Lactamase-Producing Haemophilus influenzae in Spain: Recent Emergence of Clonal Isolates with Increased Resistance to Cefotaxime and Cefixime

A β-lactamase prevalence of 23% was found among 1,730 Haemophilus influenzae isolates. Ampicillin susceptibility was 70%, and 12% of β-lactamase-negative strains presented diminished susceptibility to ampicillin (BLNAR phenotype). Susceptibility of 90% was found for cefaclor and clarithromycin, whereas it was nearly 100% for cefotaxime, cefixime, azithromycin, and cefuroxime. Ciprofloxacin-resistant (0.1%) and β-lactamase-positive amoxicillin/clavulanate-resistant (BLPACR) phenotypes (0.1%) are anecdotal so far.

Carlos Fernández-Mazarrasa

Papers

Antimicrobial susceptibilities of 1,730 Haemophilus influenzae respiratory tract isolates in Spain in 1998-1999.