Bull Soc Pathol Exot, 2004 May, 97(2), 100 - 3 {Haemophilus influenzae, the second cause of bacterial meningitis in children in Madagascar}; Razafindralambo M et al.; The Haemophilus influenzae b is one of the main germs causing bacterial meningitis in children in countries where the vaccine anti-Haemophilus influenzae b is not widely used . In Madagascar, no epidemiological study on this germ has been carried out . The objective of this research is to assess the role of Haemophilus influenzae meningitis in Antananarivo and to determine its epidemiological aspects and evolution . A multicentric study coordinated by the Institut Pasteur de Madagascar included all children less than 15 years old with infectious syndromes associated to a syndrome of meningial irritation and/or convulsion and/or coma . These children were admitted in the pediatric service of the three main hospitals in Antananarivo from June 1998 and June 2000 . A lumbar puncture was performed on each child; the cerebrospinal fluid was set aside for cytobacterial and biochemical controls completed with an antimicrobial sensitivity testing and a soluble antigens research . Out of 160 case studies, the Haemophilus influenzae b arrives at the second place among the agents causing bacterial meningitis in children . This type of bacteria is the source of 32% of meningitis after the Streptococcus pneumoniae (34%) . It affects 96% of children less than two years old, with a maximal frequency before the age of one year . The lethality rate is 28.6% and the neurological sequelae were observed in 31.4% of patients . Haemophilus influenzae is sensitive to the third generation cephalosporins but shows high resistance to chloramphenicol (42%), amoxicillin (29%) and gentamicin (22%) . The relatively high frequency as well as the high lethality rate caused by the Haemophilus influenzae b meningitis, affecting selectively the children under two years old, bring in the need to introduce the anti-Haemophilus influenzae b vaccine in the national vaccination program in Madagascar . This vaccine has proved to be efficient in many countries where it has been used . Furthermore, in the probabilistic treatment of bacterial meningitis in children, the third generation cephalosporins should be used in the first place. Proc Natl Acad Sci U S A, 2004 Jul 20, 101(29), 10644 - 9 Epub 2004 Jul 09. Protozoan predation, diversifying selection, and the evolution of antigenic diversity in Salmonella; Wildschutte H et al.; Extensive population-level genetic variability at the Salmonella rfb locus, which encodes enzymes responsible for synthesis of the O-antigen polysaccharide, is thought to have arisen through frequency-dependent selection (FDS) by means of exposure of this pathogen to host immune systems . The FDS hypothesis works well for pathogens such as Haemophilus influenzae and Neisseria meningitis, which alter the composition of their O-antigens during the course of bloodborne infections . In contrast, Salmonella remains resident in epithelial cells or macrophages during infection and does not have phase variability in its O-antigen . More importantly, Salmonella shows host-serovar specificity, whereby strains bearing certain O-antigens cause disease primarily in specific hosts; this behavior is inconsistent with FDS providing selection for the origin or maintenance of extensive polymorphism at the rfb locus . Alternatively, selective pressure may originate from the host intestinal environment itself, wherein diversifying selection mediated by protozoan predation allows for the continued existence of Salmonella able to avoid consumption by host-specific protozoa . This selective pressure would result in high population-level diversity at the Salmonella rfb locus without phase variation . We show here that intestinal protozoa recognize antigenically diverse Salmonella with different efficiencies and demonstrate that differences solely in the O-antigen are sufficient to allow for prey discrimination . Combined with observations of the differential distributions of both serotypes of bacterial species and their protozoan predators among environments, our data provides a framework for the evolution of high genetic diversity at the rfb locus and host-specific pathogenicity in Salmonella. Diagn Microbiol Infect Dis, 2004 Jul, 49(3), 201 - 9 In vitro activity of tigecycline (GAR-936) tested against 11,859 recent clinical isolates associated with community-acquired respiratory tract and gram-positive cutaneous infections; Fritsche TR et al.; Tigecycline is a novel 9-t-butylglycylamido derivative of minocycline that has demonstrated activity against a variety of bacterial pathogens, including resistant isolates, during preclinical studies . In vitro activities of tigecycline and comparators were tested against 11,859 recent (2000 and 2002) bacterial strains recovered from patients in 29 countries with community-acquired respiratory tract disease (3,317 gram-positive and -negative strains) and skin and soft tissue infections (8,542 gram-positive strains) . All oxacillin-susceptible and -resistant Staphylococcus aureus (5,077 strains; tigecycline MIC(90), 0.5 microg/mL) and coagulase-negative staphylococci (1,432 strains; MIC(90), 0.5 microg/mL), penicillin-susceptible and -resistant Streptococcus pneumoniae (1,585 strains; MIC(90), < or =0.25 microg/mL), viridans group streptococci (212 strains; MIC(90), < or =0.25-0.5 microg/mL), vancomycin-susceptible and -resistant enterococci (1,416 strains; MIC(90), 0.25-0.5 microg/mL), beta-haemolytic streptococci (405 strains; MIC(90), < or =0.25 microg/mL), beta-lactamase positive and negative Haemophilus influenzae (1,220 strains; MIC(90), 1 microg/mL), Moraxella catarrhalis (495 strains; MIC(90), 0.25 microg/mL), and Neisseria meningitidis (17 strains; MIC(90), < or =0.12 microg/mL) were inhibited by 2 microg/mL or less of tigecycline . Whereas potency of tetracycline and doxycycline markedly dropped in various resistant organism subsets, tigecycline was unaffected with an overall MIC(90) of 0.5 microg/mL . These findings confirm that tigecycline maintains a truly broad spectrum like the tetracycline class while enhancing potency . It also incorporates stability to the commonly occurring tetracycline resistance mechanisms, making it an attractive candidate for continued clinical development against pathogens causing serious community-acquired respiratory tract infections, as well as cutaneous infections. Wien Med Wochenschr, 2004 May, 154(9-10), 218 - 25 {Vaccination of the immunocompromised host}; Ullmann AJ et al.; Vaccinations are safe and effective in immunocompromised patients . Apparently most vaccines in this patient population are underutilized . General vaccination recommendations are expressed for influenza, diphtheria and tetanus . Pneumococcal, meningococcal und Haemophilus influenzae B immunizations are specially indicated for patients with or developing B-cell-deficiency . Live attenuated vaccines are usually contraindicated . The efficacy of the immunization and its indication can be additionally measured by antibody response, which is usually decreased compared to healthy subjects . Immunocompromised hosts with cancer will benefit from consistent immunization practices . Further clinical trials are urgently warranted. J Clin Microbiol, 2004 Jul, 42(7), 3065 - 72 Prevalence of the hifBC, hmw1A, hmw2A, hmwC, and hia Genes in Haemophilus influenzae Isolates; Ecevit IZ et al.; Adherence of Haemophilus influenzae to respiratory epithelial cells is the first step in the pathogenesis of H . influenzae infection and is facilitated by the action of several adhesins located on the surface of the bacteria . In this study, prevalences of hifBC, which represent the pilus gene cluster; hmw1A, hmw2A, and hmwC, which represent high-molecular-weight (HMW) adhesin genes; and hia, which represents H . influenzae adhesin (Hia) genes were determined among clinical isolates of encapsulated type b (Hib) and nonencapsulated (NTHi) H . influenzae . hifBC genes were detected in 109 of 170 (64%) Hib strains and in 46 of 162 (28%) NTHi isolates (P = 0.0001) and were more prevalent among the invasive type b strains than invasive NTHi strains (P = 0.00003) . Furthermore, hifBC genes were significantly more prevalent (P = 0.0398) among NTHi throat isolates than NTHi middle ear isolates . hmw1A, hmw2A, hmwC, and hia genes were not detected in Hib strains . Among NTHi isolates, the prevalence of hmw1A was 51%, the prevalence of hmw2A was 23%, the prevalence of hmwC was 48%, and the prevalence of hia was 33% . The hmw genes were significantly more prevalent among middle ear than throat isolates, while hia did not segregate with a respiratory tract site . These results show the variability of the presence of adhesin genes among clinical H . influenzae isolates and suggest that hemagglutinating pili may play a larger role in H . influenzae nasopharyngeal colonization than in acute otitis media whereas the HMW adhesins may be virulence factors for acute otitis media. J Antimicrob Chemother, 2004 Aug, 54(2), 393 - 400 Epub 2004 Jul 08. Inability of L22 ribosomal protein alteration to increase macrolide MICs in the absence of efflux mechanism in Haemophilus influenzae HMC-S; Peric M et al.; BACKGROUND: Haemophilus influenzae HMC-C with high-level macrolide resistance after multi-step selection by clarithromycin reverted spontaneously and became hypersusceptible to macrolides . OBJECTIVE: Determination of macrolide resistance mechanism(s) in hypersusceptible and hyperresistant strains . METHODS: The presence of macrolide efflux in the strains was studied by radioactive erythromycin accumulation . Ribosomal mutations were investigated by sequencing . The possible role of acrAB clusters in macrolide resistance was studied by sequencing and expression analysis . RESULTS: The parent strain had no ribosomal alteration, but both high-level resistant and hypersusceptible strains had R88P mutations in ribosomal protein L22 . Radioactive macrolide accumulation studies pointed to the presence of macrolide efflux in the high-level resistant and parent strains, but not in the hypersusceptible derivative . Transformation of hypersusceptible strains using total DNA from the parent strain restored the macrolide efflux system in the hypersusceptible strain, which was confirmed by MIC levels and radioactive erythromycin accumulation similar to that of the mutant resistant strain . Analysis of sequence and transcription of acrAB gene clusters showed no significant differences between resistant and hypersusceptible derivatives . CONCLUSION: Mutation in ribosomal protein L22 alone does not confer high-level macrolide resistance unless efflux is present. Appl Environ Microbiol, 2004 Jul, 70(7), 4136 - 43 Use of the riboflavin synthase gene (ribC) as a model for development of an essential gene disruption and complementation system for Haemophilus influenzae; Saeed-Kothe A et al.; We have developed a system for rapid and reliable assessment of gene essentiality in Haemophilus influenzae Rd strain KW20 . We constructed two "suicide" complementation vectors (pASK5 and pASK6) containing 5' and 3' regions of the nonessential ompP1 gene flanking a multiple cloning site and a selectable marker (a chloramphenicol resistance gene or a tetracycline resistance cassette) . Transformation of H . influenzae with the complementation constructs directs chromosomal integration of a gene of interest into the ompP1 locus, where the strong, constitutive ompP1 promoter drives its expression . This single-copy, chromosome-based complementation system is useful for confirming the essentiality of disrupted genes of interest . It allows genetic analysis in a background free of interference from any upstream or downstream genetic elements and enables conclusive assignment of essentiality . We validated this system by using the riboflavin synthase gene (ribC), a component of the riboflavin biosynthetic pathway . Our results confirmed the essentiality of ribC for survival of H . influenzae Rd strain KW20 and demonstrated that a complementing copy of ribC placed under control of the ompP1 promoter reverses the lethal phenotype of a strain with ribC deleted. J Pediatr, 2004 Jul, 145(1), 58 - 66 Safety of DTaP-based combined immunization in very-low-birth-weight premature infants: frequent but mostly benign cardiorespiratory events; Pfister RE et al.; OBJECTIVE: To evaluate the safety of diphtheria-tetanus-acellular pertussis-inactivated polio-Haemophilus influenzae type B (DTaP-IPV-HIB) immunization in premature infants . STUDY DESIGN: Observational study of 78 very low birth weight premature infants (mean gestational age, 28+/-2 weeks; mean birth weight, 1045+/-357 g) given DTaP-IPV-HIB vaccine before hospital discharge . Apnea, bradycardia, oxygen requirements and saturation, feeding practice, and medical interventions were assessed before and after immunization . The results were analyzed by the severity of the clinical condition and the persistence of prematurity-associated symptoms . RESULTS: Administration of DTaP-IPV-HIB elicited resurgence or increase in cardiorespiratory events in 47% of infants (15% had apnea, 21% had bradycardia, 42% of desaturations) . Most vaccine-triggered events resolved spontaneously or after brief stimulation . The relative risk was 5- to 8-fold higher in infants with a severe clinical course or persistence of cardiorespiratory symptoms at the time of immunization . Bag-mask respiratory support was given to 5 of 78 infants, and O(2) requirements increased transiently in 4 of 21 infants with chronic lung disease, none requiring reventilation . Reintroduction of O(2) supplementation, interruption of active oral feeding, or postponing of hospital discharge was not required . CONCLUSIONS: Cardiorespiratory events were frequently increased after DTaP-IPV-HIB immunization, requiring monitoring and appropriate intervention . However, these episodes did not have detrimental impact on the infants' clinical course . Timely immunization is warranted even in the most vulnerable preterm infants. Electrophoresis, 2004 Jul, 25(13), 1949 - 63 Capillary electrophoresis-mass spectrometry for glycoscreening in biomedical research; Zamfir A et al.; Application of capillary electrophoresis (CE) in combination with mass spectrometry (MS) and tandem MS to glycoscreening in biomedical projects is highlighted . In the first part recent CE-MS experiments by sheath liquid CE and multiple stage MS are reported . Neutral and negatively charged N-glycan mixtures from ribonuclease B and fetuin, high-mannose type N-glycoforms, oligosaccharides from lipopolysaccharides (LPS) of Haemophilus influenzae, polysaccharides of Pseudomonas aeruginosa and Staphylococcus aureus were analyzed . A particular emphasis is devoted to the applicability of novel off- and on-line CE-MS and tandem MS methods for screening of proteoglycan-derived oligosaccharides, glycosaminoglycans (GAGs), such as hyaluronates from Streptococcus agalactiae, chondroitin/dermatan sulfates (CS/DS) from bovine aorta and human skin fibroblast decorin, and heparin/heparan sulfate (HS) from porcine and bovine mucosa . The performance of CE-MS/MS for identification of glycoforms in glycopeptides and glycoproteins is illustrated by experiments performed on complex mixtures from urine of patients suffering from a hereditary N-acetylhexosaminidase deficiency (Schindler's disease) and urine of patients suffering from cancer cachexia . For determination of glycosylation patterns in glycoproteins like enzymes and antibodies by CE/MS, both CE-matrix assisted laser desorption/ionization (MALDI) and CE-electrospray ionization (ESI)-MS were functional . Finally, the potential of CE-ESI-MS strategy in glycolipid analysis is demonstrated for gangliosides from bovine brain for which particular CE buffer conditions are required. J Infect, 2004 Aug, 49(2), 115 - 25 Activity of telithromycin against key pathogens associated with community-acquired respiratory tract infections; Low DE et al.; OBJECTIVES: To investigate the correlation between in vitro susceptibility of isolates and clinical outcomes with telithromycin in respiratory tract infections . METHODS: The activity of telithromycin was determined by in vitro susceptibility testing of key respiratory tract pathogens isolated from patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute maxillary sinusitis enrolled in 14 Phase III/IV clinical trials evaluating the clinical efficacy of telithromycin . RESULTS: In this pooled analysis, telithromycin mode minimum inhibitory concentration (MIC) and MIC90, respectively, were: 0.016 and 0.03 mg/l against Streptococcus pneumoniae (n=626); 0.03 and 0.5 mg/l for penicillin-resistant S . pneumoniae (n=56); 0.03 and 1 mg/l for erythromycin-resistant S . pneumoniae (n=81); 2 and 4 mg/l against Haemophilus influenzae (including beta-lactamase producers; n=627); both 0.12 mg/l for Moraxella catarrhalis (n=159) and both 0.25 mg/l for Staphylococcus aureus (n=124) . Telithromycin (5 or 7-10 days) resulted in overall clinical and bacteriologic success rates of 88.1% (1593/1808) and 89% (1593/1789), respectively . CONCLUSIONS: High levels of in vitro susceptibility to telithromycin are paralleled by high rates of clinical cure and bacteriologic eradication. J Infect, 2004 Aug, 49(2), 109 - 14 Surveillance of the susceptibility of ocular bacterial pathogens to the fluoroquinolone gatifloxacin and other antimicrobials in Europe during 2001/2002; Morrissey I et al.; OBJECTIVES: To determine the identity of European ocular bacterial pathogens and their susceptibility to topical antimicrobial agents . METHODS: Bacterial isolates derived from clinically significant ocular infections were collected from 10 European centres . Bacteria were re-identified and susceptibility to gatifloxacin, ciprofloxacin, ofloxacin, fusidic acid, gentamicin and chloramphenicol was determined using the NCCLS agar incorporation method at a central testing laboratory . RESULTS: Five hundred and thirty-two isolates were submitted for analysis . The most common pathogen was methicillin-susceptible Staphylococcus aureus, followed by Haemophilus influenzae and Streptococcus pneumoniae . Gatifloxacin was the most potent antimicrobial agent tested for isolates from each European country as measured by pure MIC or percentage resistance (using 95% confidence intervals) . Only methicillin-resistant S . aureus was in any way refractory to the action of gatifloxacin and other fluoroquinolones . CONCLUSIONS: Fluoroquinolones offer broad-spectrum coverage for the treatment of ocular pathogens . Gatifloxacin ophthalmic solution should be a significant improvement on currently available fluoroquinolones mainly due to enhanced activity against streptococci and coagulase-negative staphylococci (which accounted for almost one-third of ocular pathogens). Arq Neuropsiquiatr, 2004 Jun, 62(2A), 250 - 2 Epub 2004 Jun 23. Etiology of bacterial meningitis among children aged 2-59 months in Salvador, Northeast Brazil, before and after routine use of Haemophilus influenzae type B vaccine; Nascimento-Carvalho CM et al.; OBJECTIVE: To describe the frequency of etiologic agents of bacterial meningitis (BM) among children aged 2-59 months in a sample of patients in Salvador, Northeast Brazil, with emphasis on the frequency of BM of unknown etiology (BMUE), just before, during and after the implementation of routine immunization of infants with Haemophilus influenzae type b (Hib) vaccination . METHOD: Demographic, clinical and cerebrospinal fluid (CSF) information was collected from the chart of every patient, aged 2-59 months, whose CSF exam was performed at the CSF Lab - Jose Silveira Foundation, between January 1989 and December 2001 . Every CSF exam was completely performed according to standard methods . The etiologic diagnosis was based on either culture and/or latex-agglutination test . When the agent was only seen on Gram stained smear, the diagnosis was descriptive . BMUE was defined as: glucose < 40mg / dl, protein > 100 mg / dl, white blood cell count > 20 cells / mm(3), percentage of neutrophils > 80% . RESULTS: Of 1519 patients, 894 (58.9%) had normal exams and BM was diagnosed in 95 (6.2%) . Etiologic agents were: Hib (44.2%), meningococcus (13.7%), Gram-negative bacilli (11.6%), Mycobacterium tuberculosis (6.3%), pneumococcus (4.2%), other agents (4.2%); BMUE was diagnosed in 15.8% of cases with BM . By analysing the frequency of BMUE and Hib among all exams performed yearly, the peaks were recorded in 1989 (5.3%) and 1990 (16.9%), respectively, decreasing to 0.7% and 0% in 2001 . CONCLUSION: It is possible that the implementation of the conjugate Hib vaccine during the 1990's has been decreasing not only the occurrence of Hib meningitis but also of BMUE. APMIS, 2004 Apr-May, 112(4-5), 299 - 303 Antibody response to the patient's own Haemophilus influenzae isolate can support the aetiology in lower respiratory tract infections; Stralin K et al.; In order to understand the clinical importance of Haemophilus influenzae isolated from sputum samples, an indirect immunofluorescence (IF) assay was developed, using the patient's own isolate as the antigen . The method was tested on samples from six patients with lower respiratory tract infection (LRTI) and H . influenzae isolated from blood (n=2), sputum (n=3) or both (n=1), and on two healthy adults with H . influenzae isolated from the nasopharynx . Between acute and convalescent sera, a four-fold IgG antibody increase was achieved in five of six LRTI patients, including the three blood culture-positive patients . One LRTI patient and the two asymptomatic carriers showed stable antibody levels against their own isolate . Although small, the study indicates that indirect IF can be a promising tool for determining whether a H . influenzae strain represents the probable cause of infection or just a strain colonising the airways . More extensive studies should be performed in order to establish the usefulness of the assay. J Trop Pediatr, 2004 Jun, 50(3), 158 - 63 The causes of hospital admission and death among children in Bamako, Mali; Campbell JD et al.; The health burden and mortality caused by infections during childhood remain large in sub-Saharan Africa . We performed a review of the causes of hospitalization and death among children admitted to a pediatric teaching hospital in Bamako, Mali . Medical records of children admitted throughout 2000 were systematically sampled and abstracted for demographics, diagnosis, hospital course, and disposition . A sample of 1644 charts, from 5001 admitted children, were abstracted . The median age was 8 months . Half of the children had a febrile illness . All diagnoses were made clinically . The annual incidence per 100,000 and case fatality rates of the four most common serious infections, excluding malaria, were as follows: pneumonia, 165 (12 per cent); sepsis, 75 (37 per cent); meningitis, 71 (20 per cent); and enteric fever, 14 (12 per cent) . An estimated 1300 children were admitted with thick-smear confirmed malaria; at least 64 per cent met World Health Organization criteria for severe malaria and 11 per cent died . Seventy-one per cent of admissions were due to infections . Overall 21 per cent of children admitted died in the hospital, most within the first 3 days of admission . Infectious diseases remain the primary cause of hospitalization among Malian children and frequently lead to death . A substantial proportion of this morbidity and mortality is probably attributable to vaccine-preventable diseases, such as Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis . Prospective surveillance using microbiological data is needed to delineate the organism-specific burdens. J Trop Pediatr, 2004 Jun, 50(3), 131 - 6 Haemophilus type B meningitis in Saudi children under 5 years old; Al-Mazrou YY et al.; This study was designed to determine the magnitude of bacterial meningitis in general and Hib meningitis in particular among children below the age of 5 years . A population-based, prospective descriptive and analytical study was conducted in five regions, one each in northern, southern, eastern, western, and central parts of Saudi Arabia . Active surveillance for cases of bacterial meningitis among the study population, which comprised 171,818 children under 5 years of age, was implemented . A total of 208 cases of meningitis were identified, of which 141 (67.8 per cent) were identified with a definite causative organism . The remaining 67 cases (32 per cent) were labeled as aseptic meningitis . The overall incidence of meningitis was 60.53/10(5) in under-fives with a disease spectrum similar to that reported in studies conducted in other countries . The three leading causes of meningitis were Hib (Haemophilus influenzae type B), MCM (Neisseria menigitides) and SPN (Streptococcus pneumoniae) . Hib meningitis constituted 28 per cent of cases with an incidence rate of 16.88/10(5) children . There was a marked regional variation in Hib incidence . MCM was the second leading cause (18 per cent) of meningitis with an incidence of 10.77/10(5) while SPN comprised 11 per cent of cases and its incidence was 9.69/10(5) . Almost all MCM cases were related to meningitis outbreaks that occurred in Saudi Arabia during two successive Hajj seasons (2000-2001) . Hib cases showed a bimodal seasonality, one peak during March-May, the other during September-November . The fact that this study is the first national base-line data on meningitis in general and Hib incidence in particular, has augmented further justification for introducing Hib vaccine within the national Expanded Program on Immunization (EPI) . Based on the experience gained during this study regarding surveillance of meningitis disease, optimal methods to strengthen meningitis surveillance were identified . A model of Meningitis Diseases Surveillance was generated that can be tested and then generalized . The study has documented beyond doubt the impact of Hajj seasons on MCM disease occurrence and further justifies the rigorous control and preventive measures being taken in this aspect. Pediatrics, 2004 Jul, 114(1), 187 - 95 Children who have received no vaccines: who are they and where do they live? Smith PJ, Chu SY, Barker LE. CONTEXT: Each year 2.1 million children 19 to 35 months of age are undervaccinated . Among these are children who have received no vaccinations . Unvaccinated children are at increased risk of acquiring and transmitting vaccine-preventable diseases . OBJECTIVES: To assess whether the characteristics of children with no vaccinations differ from those of undervaccinated children, to monitor trends in the numbers of unvaccinated children, and to identify states with high rates and counties with large numbers of unvaccinated children . DESIGN: A nationally representative probability sample of children 19 to 35 months of age was collected annually between 1995 and 2001 . Vaccination histories were ascertained from children's medical providers . Undervaccinated children had received > or =1 dose of diphtheria-tetanus-pertussis, polio, measles, Haemophilus influenzae type b, hepatitis B, or varicella vaccine but were not fully vaccinated . Unvaccinated children were children who were reported as having no medical providers and having received no vaccinations or children whose medical providers reported administering no vaccinations . PARTICIPANTS: A total of 151,720 children sampled between 1995 and 2001, 795 of whom were unvaccinated . RESULTS: Undervaccinated children tended to be black, to have a younger mother who was not married and did not have a college degree, to live in a household near the poverty level, and to live in a central city . Unvaccinated children tended to be white, to have a mother who was married and had a college degree, to live in a household with an annual income exceeding 75,000 dollars, and to have parents who expressed concerns regarding the safety of vaccines and indicated that medical doctors have little influence over vaccination decisions for their children . Unvaccinated children were more likely to be male than female . Annually, approximately 17,000 children were unvaccinated . The largest numbers of unvaccinated children lived in counties in California, Illinois, New York, Washington, Pennsylvania, Texas, Oklahoma, Colorado, Utah, and Michigan . States that allowed philosophical exemptions to laws mandating vaccinations for children as they entered school had significantly higher estimated rates of unvaccinated children . CONCLUSIONS: Unvaccinated children have characteristics that are distinctly different from those of undervaccinated children . Unvaccinated children are clustered geographically, increasing the risk of transmitting vaccine-preventable diseases to both unvaccinated and undervaccinated children. J Bacteriol, 2004 Jul, 186(14), 4575 - 84 Mu-like prophage strong gyrase site sequences: analysis of properties required for promoting efficient mu DNA replication; Oram M et al.; The bacteriophage Mu genome contains a centrally located strong gyrase site (SGS) that is required for efficient prophage replication . To aid in studying the unusual properties of the SGS, we sought other gyrase sites that might be able to substitute for the SGS in Mu replication . Five candidate sites were obtained by PCR from Mu-like prophage sequences present in Escherichia coli O157:H7 Sakai, Haemophilus influenzae Rd, Salmonella enterica serovar Typhi CT18, and two strains of Neisseria meningitidis . Each of the sites was used to replace the natural Mu SGS to form recombinant prophages, and the effects on Mu replication and host lysis were determined . The site from the E . coli prophage supported markedly enhanced replication and host lysis over that observed with a Mu derivative lacking the SGS, those from the N . meningitidis prophages allowed a small enhancement, and the sites from the Haemophilus and Salmonella prophages gave none . Each of the candidate sites was cleaved specifically by E . coli DNA gyrase both in vitro and in vivo . Supercoiling assays performed in vitro, with the five sites or the Mu SGS individually cloned into a pUC19 reporter plasmid, showed that the Mu SGS and the E . coli or N . meningitidis sequences allowed an enhancement of processive, gyrase-dependent supercoiling, whereas the H . influenzae or Salmonella serovar Typhi sequences did not . While consistent with a requirement for enhanced processivity of supercoiling for a site to function in Mu replication, these data suggest that other factors are also important . The relevance of these observations to an understanding of the function of the SGS is discussed . Proteins, 2004 Aug 15, 56(3), 564 - 71 Novel structure and nucleotide binding properties of HI1480 from Haemophilus influenzae: a protein with no known sequence homologues; Lim K et al.; The crystal structure of the Haemophilus influenzae protein HI1480 was determined at 2.1-A resolution . The amino acid sequence of HI1480 is unique, having no homology with other known protein sequences . The protein adopts a novel alpha+beta fold, and associates into a dimer of tightly associated dimers . The tight dimers are formed by intermolecular interactions that are mediated by an antiparallel beta-barrel involving both monomers . Helical regions of two dimers mediate the tetramer formation . The helical region contains a four-helix bundle that has been seen only in the anticodon binding domains of class I tRNA synthetases . A cluster of four residues, Tyr18, Arg134, Glu26, and Lys12 is located in a depression formed at the four-helix bundle/ beta-barrel interface . The arrangement is suggestive of an active center, possibly a catalytic site . The HI1480 gene is located within the Mu-like prophage region of H . influenzae, has no homology to bacteriophage genes, and is flanked by transposases . Hence, this is an example of horizontal transfer from an unknown organism . Gel mobility shift assays revealed that HI1480 binds DNA and RNA molecules . Double-stranded DNA is favored over single-stranded DNA, and longer DNA molecules are bound better than shorter ones . Enferm Infecc Microbiol Clin, 2004 Jun-Jul, 22(6), 323 - 7 {Activity of telithromycin and other oral antibiotics against respiratory tract pathogens with acquired mechanisms of resistance}; Gomez-Garces JL et al.; INTRODUCTION: Antimicrobial resistance among strains of Streptococcus pneumoniae, Haemophilus influenza, and Streptococcus pyogenes has limited the usefulness of conventional agents for the treatment of some infectious diseases related with these microorganisms . There is thus a clear need for new antimicrobial agents active against these resistant strains . OBJECTIVES: To assess the in vitro susceptibility to telithromycin and other oral antimicrobial agents of 307 strains of S . pneumoniae, H . influenzae, and S . pyogenes with acquired mechanisms of resistance to macrolides and/or beta-lactams . METHODS: Antimicrobial susceptibility testing was performed by the agar dilution method, and results were preferentially evaluated according to National Committee for Clinical Laboratory Standards (NCCLS) guidelines . RESULTS: The activity of telithromycin against erythromycin-resistant S . pneumoniae was excellent . All the strains were inhibited with 2 mg/l, regardless of the mechanism of macrolide resistance exhibited . Telithromycin was slightly more active than the tested macrolides in beta-lactamase-producing H . influenzae strains, with a MIC90 of 2 mg/l . Telithromycin also demonstrated potent activity against macrolide-resistant S . pyogenes . The MIC of telithromycin was > 4 mg/l for only one out of the 202 tested strains . CONCLUSIONS: Telithromycin is a very promising therapeutic option against bacterial pathogens of the respiratory tract, including strains that have developed mechanisms of resistance to macrolides and/or beta-lactams. Mol Microbiol, 2004 Jul, 53(2), 651 - 64 Inactivation of deoxyadenosine methyltransferase (dam) attenuates Haemophilus influenzae virulence; Watson ME Jr et al.; Mutants in deoxyadenosine methyltransferase (dam) from many Gram-negative pathogens suggest multiple roles for Dam methylase: directing post-replicative DNA mismatch repair to the correct strand, guiding the temporal control of DNA replication and regulating the expression of multiple genes (including virulence factors) by differential promoter methylation . Dam methylase (HI0209) in strain Rd KW20 was inactivated in Haemophilus influenzae strains Rd KW20, Strain 12 and INT-1; restriction with Dam methylation-sensitive enzymes DpnI and DpnII confirmed the absence of Dam methylation, which was restored by complementation with a single copy of dam ectopically expressed in cis . Despite the lack of increased mutation frequency, the dam mutants had a 2-aminopurine-susceptible phenotype that could be suppressed by secondary mutations in mutS, suggesting a role for Dam in H . influenzae DNA mismatch repair . Invasion of human brain microvascular endothelial cells (HBMECs) and human respiratory epithelial cells (NCI-H292) by the dam mutants was significantly attenuated in all strains, suggesting the absence of a Dam-regulated event necessary for uptake or invasion of host cells . Intracellular replication was inhibited only in the Strain 12 dam mutant, whereas in the infant rat model of infection, the INT-1 dam mutant was less virulent . Dam activity appears to be necessary for both in vitro and in vivo virulence in a strain-dependent fashion and may function as a regulator of gene expression including virulence factors. Klin Mikrobiol Infekc Lek, 2004 Jun, 10(3), 130 - 133 {Diagnostics of invasive meningococcal, haemophilus and pneumococcal disease by PCR assay}; Kalmusova J et al.; Objectives: Development of extended polymerase chain reaction (PCR) for non-culture detection of Nesseria meningitidis, Haemophilus influenzae and Streptococcus pneumonie from invasive infections . Materials and methods: A method of PCR was optimalised on strains of Nesseria meningitidis, Haemophilus influenzae b and Streptococcus pneumonie . Detection of pathogens was evaluated on 230 samples from patiens with invasive infection . Results: Positive results of PCR were found in 103 samples of 230 (44.7 %) . The percentage of positivity was higher in CSF samples (57.0 %) than in serum (33.8 %) or blood (33.3 %) samples . Conclusion: PCR method enables etiological diagnostics in cases, where antibiotic treatment was started . PCR results are available earlier than the results of cultivation . Multilocus sequence typing (MLST) of PCR products enables clonal analysis of etiological agents even in cases with negative results of cultivation. Klin Mikrobiol Infekc Lek, 2004 Jun, 10(3), 118 - 123 {The effect of routine vaccination in the Czech Republic on the incidence of invasive diseases caused by Haemophilus influenzae b}; Krizova P et al.; Objectives: The paper is an analysis of the results of a five-year surveillance programme in the Czech Republic (1999-2003); it evaluates the efficacy of routine Hib vaccination that started in July 2001 . Material and methods: Morbidity due to Hib was explored in a surveillance programme, which since 2002 also included the investigation of Hib vaccine failure . Hib identification was carried out with standard methods, serotypes were verified using PCR, biotyping was carried out in all strains and in selected strains also multilocus sequential typing . Results: In the years 1999-2003 invasive Hib disease presented mostly as meningitis, followed by epiglottitis . Mortality due to an invasive Hib disease was in the years 1999-2003 2.3 % . Among the Hib strains isolated in invasive disorders predominated the biotype I and the sequence type ST-6 . Conclusions: Following the introduction of routine Hib vaccination in the Czech Republic there was an overall drop in morbidity due to Hib invasive disorders . This was most obvious in a decrease in the morbidity of Hib meningitis and in the vaccinated age group . Two years after the introduction of routine Hib vaccination morbidity dropped by 81 % in children aged 0 to 1 year . In higher age groups there was no change in the number of invasive Hib disease . Neither was there an increase in "non-b" haemophilus invasive disorders . Failure of Hib vaccination is a rare occurence. J Biol Chem, 2004 Aug 27, 279(35), 36171 - 4 Epub 2004 Jun 28. NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway; Jono H et al.; The transcription factor NF-kappaB regulates genes involved in inflammatory and immune responses, tumorigenesis, and apoptosis . In contrast to the pleiotropic stimuli that lead to its positive regulation, the known signaling mechanisms that underlie the negative regulation of NF-kappaB are very few . Recent studies have identified the tumor suppressor CYLD, loss of which causes a benign human syndrome called cylindromatosis, as a key negative regulator for NF-kappaB signaling by deubiquitinating tumor necrosis factor (TNF) receptor-associated factor (TRAF) 2, TRAF6, and NEMO (NF-kappaB essential modulator, also known as IkappaB kinase gamma) . However, how CYLD is regulated remains unknown . The present study revealed a novel autoregulatory feedback pathway through which activation of NF-kappaB by TNF-alpha and bacterium nontypeable Haemophilus influenzae (NTHi) induces CYLD that in turn leads to the negative regulation of NF-kappaB signaling . In addition, TRAF2 and TRAF6 appear to be differentially involved in NF-kappaB-dependent induction of CYLD by TNF-alpha and NTHi . These findings provide novel insights into the autoregulation of NF-kappaB activation. Int J Antimicrob Agents, 2004 Jul, 24(1), 18 - 23 Use of oral cephalosporins in the treatment of acute otitis media in children; Brook I; The selection of the most effective antimicrobial to treat acute otitis media (AOM) has become more difficult in recent years because of increasing antibiotic resistance among all AOM pathogens . Resistance of Streptococcus pneumoniae to penicillin as well as amoxicillin ranges from 30 to 55% in the USA . Currently, 40-55% of Haemophilus influenzae and 90-100% of Moraxella catarrhalis are resistant to penicillin because of the production of Beta-lactamases . This review discusses the availability of oral cephalosporins that can be utilised for the treatment of AOM in children . An evaluation is made regarding their in vitro activity against the pathogens, their middle-ear concentrations, pharmacokinetics and pharmacodynamics (PK/PD) . The cephalosporins that will be discussed are cefuroxime-axetil, cefprozil, cefdinir and cefpodoxime-proxetil . The current recommendations for therapy of AOM limit the choices of clinicians to a single cephalosporin (cefuroxime-axetil) . However, clinical, bacteriological and PK/PD data shows that several other cephalosporins (cefprozil, cefdinir and cefpodoxime-proxetil) possess similar indices which provide the clinician with wider therapeutic choices that can insure better compliance and ultimately better success in eradication of the infection. Med Trop (Mars), 2004, 64(1), 33 - 8 {Role of thiamphenicol in the treatment of community-acquired lung infections}; Raymond J et al.; Streptococcus pneumoniae and Haemophilus influenzae are the two main pathogens responsible for bacterial respiratory tract infections . Their antimicrobial susceptibility to antibiotics like beta-lactams, macrolides or fluoroquinolones has been largely studied, while it remains less known to other antibiotics like thiamphenicol, erythromycin, cotrimoxazole or tetracycline, often used in developing countries due to their availability . In this study, the activity of chloramphenicol and thiamphenicol on different respiratory tract pathogens was found to be equivalent . However, thiamphenicol was better in detecting resistant organisms . One hundred S . pneumoniae among which 69% had reduced susceptibility to penicillin (PRSP) and 87 H . influenzae isolates, 39.1% producing beta-lactamase, were recovered from sputum cultures in children . All H . influenzae and all penicillin susceptible S . pneumoniae strains were sensitive to thiamphenicol . Susceptibility of penicillin sensitive S . pneumoniae to erythromycin, cotrimoxazole and tetracycline was 70.9%, 83.9%, and 90.3% respectively . Susceptibility of PRSP to thiamphenicol, erythromycin, cotrimoxazole and tetracycline was 68.1%, 7.2%, 17.4% and 44.9% respectively . Thiamphenicol and chloramphenicol are still active against respiratory pathogens. Biometals, 2004 Jun, 17(3), 235 - 43 Lactoferrin receptors in gram-negative bacteria: insights into the iron acquisition process; Ekins A et al.; One component of the anti-microbial function of lactoferrin (Lf) is its ability to sequester iron from potential pathogens . To overcome this iron limitation, a number of gram-negative bacterial pathogens have developed a mechanism for acquiring iron directly from this host glycoprotein . This mechanism involves surface receptors capable of specifically binding Lf from the host, removing iron and transporting it across the outer membrane . The iron is then bound by a periplasmic iron-binding protein, FbpA, and transported into the cell via an inner membrane complex comprised of FbpB and FbpC . The receptor has been shown to consist of two proteins, LbpA and LbpB . LbpB is bilobed lipoprotein anchored to the outer membrane via fatty acyl groups attached to the N-terminal cysteine . LbpA is a homologue of siderophore receptors, which consist of an N-terminal plug and a C-terminal beta-barrel region . We propose that the receptor proteins, LbpA and LbpB, induce conformational changes in human Lf (hLf) that lower its affinity for iron that binding by FbpA can drive the transport across the outer membrane, a mechanism shared with transferrin (Tf) receptors . The interaction between the receptor proteins and Lf is quite extensive and has been previously studied by using chimeric proteins comprised of Lf & Tf . In an attempt to evaluate the role of FbpA in the transport process, a series of site-directed mutants of FbpA were prepared and used to replace the wild-type protein in the iron acquisition pathway . The mutations were made in the iron-binding and anion-binding ligands of FbpA and were designed to result in altered binding properties . Protein crystallography of the iron-bound form of the Q58L mutant protein revealed that it was in the open conformation with iron coordinated by Y195 and Y196 from the C-terminal domain but not by the other iron-liganding amino acids from the N-terminal domain, H9 and E57 . Replacement of the native FbpA in Neisseria meningitidis with wild-type or mutant Haemophilus influenzae FbpAs resulted in a defect in growth on Tf or Lf, suggesting that there may be a barrier to functional expression of H . influenzae FbpAs in Neisseria meningitidis . Thus mutants of the N . meningitidis FbpA are being prepared to replace wild-type protein in order to test their ability to mediate transport from hLf. J Microbiol Immunol Infect, 2004 Jun, 37(3), 164 - 8 Epidemiology of Haemophilus influenzae type b meningitis in Taiwan, 1997 and 2000; Shao PL et al.; In order to determine the incidence of Haemophilus influenzae type b (Hib) meningitis in Taiwan, we analyzed the National Health Insurance Research Database (NHIRD) . We identified cases that were younger than 5 years old and diagnosed with Hib meningitis from the NHIRD in both 1997 and 2000 . Sixteen and 8 children with Hib meningitis were identified in the NHIRD for 1997 and 2000, respectively . The majority of cases were 2 years old and under . The overall fatality rate was 8.33% . Assuming similar proportions of Hib meningitis in cases of meningitis with identified causes and meningitis without identified causes, the annual incidence of Hib meningitis in children younger than 5 years old was estimated to be 5.57 and 3.22 per 100,000 in years 1997 and 2000, respectively . The incidence of Hib meningitis in Taiwan is lower than in western countries and other Asian countries . This is consistent with the notion that Hib meningitis incidence is low in Chinese populations . The decline in incidence from 1997 to 2000 is likely a result of the introduction of a self-paid Hib vaccine in Taiwan, starting in 1993 . The availability of the NHIRD provides an extra tool for the epidemiological study of infectious diseases in Taiwan and can be valuable for similar studies. Pulm Pharmacol Ther, 2004, 17(4), 199 - 203 Ertapenem as initial antimicrobial monotherapy for patients with chronic obstructive pulmonary disease hospitalized with typical community-acquired pneumonia; Friedland IR et al.; This report describes a post-hoc analysis of two large studies of typical community-acquired pneumonia (CAP) in hospitalized patients, focusing on demographics, disease characteristics, and outcome in patients with and without chronic obstructive pulmonary disease (COPD) . In both studies, ertapenem 1 g IV daily was compared with ceftriaxone 1 g IV daily as initial antimicrobial therapy . Clinically improving patients could be switched to oral antibiotic therapy after 3 days . Of the 857 patients treated in both studies, 264 (31%) had COPD . The proportions of patients who were male, were >/=65 years of age, had a Pneumonia Severity Index of IV/V, or had Haemophilus influenzae isolated in a baseline culture were higher in patients with COPD . Streptococcus pneumoniae was the most common pathogen both in patients with and without COPD . Clinical response rates in assessable patients 7-14 days after completion of therapy for the combined treatment groups were 90% (187/208) for patients with COPD and 93% (424/456) for those without COPD (odds ratio 0.7 {95% CI, 0.4-1.2}, P = 0.17) . Of assessable COPD patients, 109/121 (90%) treated with ertapenem and 78/87 (90%) treated with ceftriaxone achieved a favorable clinical response (odds ratio 1.0 {95% CI, 0.6-1.8}, P = 0.94) . The outcome in patients with or without COPD was similar regardless of therapy . In patients with COPD as well as in the overall study population, the efficacy of ertapenem as initial antimicrobial monotherapy for patients with serious typical community-acquired pneumonia was comparable to that of ceftriaxone. Jpn J Antibiot, 2004 Apr, 57(2), 187 - 95 {The isolation frequency and antimicrobial susceptibility of Haemophilus influenzae isolated in Saga University Hospital}; Fukutomi Y et al.; Isolation frequency and antimicrobial susceptibility of Haemophilus influenzae isolated in Saga University hospital from October 2002 to September 2003 were investigated . Out of 155 H . influenzae strains subjected 77 were isolated from pediatrics specimens . beta-Lactamase negative ampicillin (ABPC)-resistant H . influenzae (BLNAR), against which MICs of ABPC were higher than 4 microg/mL, were 32 strains (20.6%), and it became 63 strains (41.3%) when Low-BLNAR, against which MICs of ABPC were higher than 2 microg/mL, were included . beta-Lactamase positive ABPC-resistant H . influenzae (BLPAR) were 8 strains (5.2%) . Although those BLNAR were also resistant to variety of beta-lactams, fluoroquinolones and other antibiotics were not affected by the level of ABPC-resistance . Resistant strains of BLPAR against SBT/ABPC, a combination of a beta-lactamase inhibitor, were detected but all of them were sensitive to TAZ/PIPC, an another combination . Those strains were able to be considered as beta-lactamase positive amoxicillin-clavulanate resistant H . influenzae (BLPACR) . PIPC, TAZ/PIPC, CTRX, CDTR, MEPM, LVFX and CPFX showed good activity among tested antibiotics. Jpn J Antibiot, 2004 Apr, 57(2), 157 - 71 {Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa isolated in major hospitals in Nagano prefecture}; Hachiya T et al.; We determined the minimum inhibitory concentration (MIC) of various antimicrobial agents against 140 strains of Streptococcus pneumoniae, 131 strains of Haemophilus influenzae and 178 strains of Pseudomonas aeruginosa isolated from respiratory organs in 28 affiliated hospitals in Nagano prefecture between December 2002 and February 2003 . The results of this report were as followed: 1 . All 140 strains of S . pneumoniae were classified into 3 groups; penicillin-susceptible S . pneumoniae (PSSP) (47.1%), penicillin-intermediate S . pneumoniae (PISP) (43.6%) and penicillin-resistant S . pneumoniae (PRSP) (9.3%) . 2 . Carbapenems and glycopeptide (vancomycin) had highly potent antimicrobial activity against PISP and PRSP like PSSP . However, some of PISP or PRSP isolates were resistant to cephalosporins and a fluoroquinolone (levofloxacin) . 3 . All 131 strains ofH . Influenzae were also classified into three groups; ampicillin sensitive H . influenzae (73.3%), beta-lactamase producing ampicillin resistant H . influenzae (BLPAR) (8.4%) and beta-lactamase negative ampicillin resistant H . influenzae (BLNAR) (18.3%) . 4 . Carbapenems and a fluoroquinolone had highly potent antimicrobial activity against BLPAR and BLNAR . However, there were clear differences among 4 carbapenems for the antimicrobial activity . Ceftriaxone (CTRX) was the most active among cepharosporins in this study . 5 . The rate of P . aeruginosa isolates resistant to carbapenems, a fluoroquinolone and aminoglycosides were about 11 to approximately 16%, 15% and 0.6 to approximately 8%, respectively . None of the strains was resistant to all 3 antimicrobial classes, but 3 strains were resistant to combination of 2 classes . 6 . The MIC50 and MIC90 values of various antibiotics against S . pneumoniae, H . influenzae and P . aeruginosa were different in all 4 regions . In conclusion, the antimicrobial surveillance programs are important for guiding empiric therapy and for focusing interventional control of antimicrobial resistance in regions and hospitals. Przegl Epidemiol, 2004, 58(1), 57 - 65 {Meningitis and encephalitis in Poland in 2002}; Rosinska M et al.; In Poland, 861 cases of bacterial meningitis and encephalitis, 307 cases of viral encephalitis, 1022 of viral meningitis and 286 cases of meningitis and encephalitis of other or unknown etiology were reported in 2002 . Incidence of the bacterial central nervous system infections has been declining over the past decade and the level of viral infections, following the outbreak in the mid-nineties, remained stable . Etiological factor was determined in 365 (42%) cases of bacterial meningitis/encephalitis . Among them Neisseria meningitidis was found in 90 cases, Haemophilus influenzae in 72 cases and Streptococcus pneumoniae in 85 cases . As in the past type B was the predominant type of N . meningitidis cultured from the patients, but type C appears to be on the rise accounting for 35% of the serotyped strains . 126 cases of tick borne encephalitis were reported in Poland in 2002, most of them from endemic areas of north-eastern part of the country. J Antibiot (Tokyo), 2004 Apr, 57(4), 280 - 8 In vitro microbiological characterization of a novel azalide, two triamilides and an azalide ketal against bovine and porcine respiratory pathogens; Norcia LJ et al.; Several novel 15-membered-ring macrolide agents (azalide 1, triamilides 2 and 3, and the azalide 3,6-ketal 4) were identified as potential antibacterial agents against Mannheimia (formerly named as Pasteurella) haemolytica, Pasteurella multocida, Haemophilus somnus and Actinobacillus pleuropneumoniae, important etiological agents of bovine and porcine respiratory disease . Compound 3 is the major component of the antibiotic tulathromycin . Antibacterial activity against tilmicosin-resistant P . multocida field isolates was also tested . In vitro MIC 50/90 analysis revealed that the four newly synthesized compounds were more potent than tilmicosin against M . haemolytica (4 to approximately 8x), P . multocida (8 to approximately 16x), A . pleuropneumoniae (4x), H . somnus (2x and 16x), and tilmicosin-resistant P . multocida (32x) . In time-kill kinetic studies, all four novel compounds and tilmicosin showed bactericidal activity against M . haemolytica, P . multocida and A . pleuropneumoniae at both 4x and 8x MIC . A functional assay using genetically defined mutants revealed that all four novel compounds were poorer substrates for the efflux pump, AcrA/B system, than tilmicosin . A pH study using LPS mutants indicated that the enhanced in vitro potency of the triamilides, particularly compound 3 was mainly due to better penetration of the molecule through the outer membrane . The third amine group at the C-4'' position of the triamilde molecules contributed to this increased membrane penetration by increasing overall basicity . These studies indicate that the four novel compounds have potential as antibacterial agents against bovine and porcine respiratory disease. J Antimicrob Chemother, 2004 Aug, 54(2), 542 - 5 Epub 2004 Jun 23. Selection of resistance of telithromycin against Haemophilus influenzae, Moraxella catarrhalis and streptococci in comparison with macrolides; Drago L et al.; OBJECTIVE: The in vitro abilities of telithromycin, azithromycin and clarithromycin to select for resistance were compared by testing isolates of Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and beta-haemolytic streptococci . METHODS: Five strains each of beta-lactamase-positive and beta-lactamase-negative H . influenzae, beta-lactamase-positive and beta-lactamase-negative M . catarrhalis, S . pneumoniae, beta-haemolytic group A, group C and group G streptococci and three strains of beta-lactamase-negative ampicillin-resistant H . influenzae were evaluated . Development of resistance was determined by multi-step and single-step methodologies . For multi-step studies, MIC values were determined after five serial passages on antibiotic-gradient plates and after 10 serial passages on antibiotic-free plates . Acquisition of resistance was defined as an increase of >/=4-fold from the starting MIC . In single-step studies, the rate of spontaneous mutations was calculated after a passage on plates containing antibiotics at concentrations equal to the highest NCCLS breakpoints . RESULTS: Azithromycin, clarithromycin and telithromycin gave a >/=4-fold increase in 20, 20 and 10 streptococcus strains, in 4, 5 and 0 H . influenzae strains and in 2, 7 and 4 M . catarrhalis strains, respectively . After 10 passages on antibiotic-free plates, 21/26 strains for azithromycin, 22/32 for clarithromycin and 1/14 for telithromycin maintained high MIC values . In single-step studies, the frequency of mutations was <10(-10) for H . influenzae and M . catarrhalis for telithromycin, azithromycin and clarithromycin . Telithromycin induced mutations at a lower rate than azithromycin and clarithromycin in streptococcal strains . CONCLUSION: Telithromycin showed a very limited ability to select for resistance in respiratory pathogens compared with azithromycin and clarithromycin. Antimicrob Agents Chemother, 2004 Jul, 48(7), 2599 - 603 Antibacterial effects of amoxicillin-clavulanate against Streptococcus pneumoniae and Haemophilus influenzae strains for which MICs are high, in an in vitro pharmacokinetic model; MacGowan AP et al.; The antibacterial effect of amoxicillin-clavulanate in two formulations, pharmacokinetically enhanced 16:1 amoxicillin-clavulanate twice a day (b.i.d.) and standard 7:1 amoxicillin-clavulanate b.i.d., were studied in an in vitro pharmacokinetic model of infection . Five strains of Streptococcus pneumoniae and two of Haemophilus influenzae, all associated with raised MICs (2 to 8 mg/liter), were used . The antibacterial effect was measured over 24 h by the area under the bacterial kill curve (AUBKC) and the log change in viable count at 24 h (Delta24) . A high 10(8) CFU/ml and low 10(6) CFU/ml initial inocula were used . Employing the Delta24 effect measure, the time above MIC (T>MIC) 50% maximum effect (EC(50)) for S . pneumoniae was in the range 21 to 28% with an 80% maximal response of 41 to 51%, for the AUBKC measure, the value was 26 to 39%, irrespective of inoculum . For H . influenzae, the T>MIC EC(50) was 28 to 37%, and the 80% maximum response was 32 to 48% for the Delta24 measure and 20 to 48% for AUBKC . The maximum response occurred at a T>MIC of 50 to 60% for both species and inocula . The S . pneumoniae data were analyzed by analysis of variance to assess the effect of inoculum, formulation, and MIC on antibacterial effect . Standard and enhanced formulations had different effects depending on MIC, with the standard formulation less effective at higher amoxicillin-clavulanate MICs . This is explained by the greater T>MICs of the enhanced formulation . Although resistant to amoxicillin-clavulanate by conventional breakpoints, S . pneumoniae and H . influenzae strains for which MICs are 2 or 4 mg/liter may well respond to therapy with pharmacokinetically enhanced formulation amoxicillin-clavulanate. Drugs, 2004, 64(13), 1433 - 64 Cefdinir: a review of its use in the management of mild-to-moderate bacterial infections; Perry CM et al.; Cefdinir (Omnicef) is an oral third-generation cephalosporin with good in vitro activity against many pathogens commonly causative in community-acquired infections . The drug provides good coverage against Haemophilus influenzae, Moraxella catarrhalis and penicillin-susceptible Streptococcus pneumoniae, the most common respiratory tract pathogens . Cefdinir is stable to hydrolysis by commonly occurring plasmid-mediated beta-lactamases and retains good activity against beta-lactamase-producing strains of H . influenzae and M . catarrhalis . The drug distributes into various tissues (e.g . sinus and tonsil) and fluids (e.g . middle ear), and has a pharmacokinetic profile that allows for once- or twice-daily administration.Cefdinir, administered for 5 or 10 days, has shown good clinical and bacteriological efficacy in the treatment of a wide range of mild-to-moderate infections of the respiratory tract and skin in adults, adolescents and paediatric patients in randomised, controlled trials . In adults and adolescents, cefdinir is an effective treatment for both lower (acute bacterial exacerbations of chronic bronchitis {ABECB}, community-acquired pneumonia) and upper (acute bacterial rhinosinusitis, streptococcal pharyngitis) respiratory tract infections, and uncomplicated skin infections . Its bacteriological and clinical efficacy in patients with lower respiratory tract infections was equivalent to that of comparator agents (cefprozil {bacteriological only}, loracarbef, cefuroxime axetil and cefaclor) . In one trial in patients with ABECB, cefdinir produced a higher rate of clinical cure than cefprozil (95% CIs indicated nonequivalence) . Cefdinir also produced good clinical and bacteriological responses equivalent to responses with amoxicillin/clavulanic acid in patients with acute bacterial rhinosinusitis . In addition, it was at least as effective as penicillin V (phenoxymethylpenicillin) in streptococcal pharyngitis/tonsillitis and as effective as cefalexin in uncomplicated skin infections . In paediatric patients aged > or =6 months, cefdinir showed similar efficacy to that of amoxicillin/clavulanic acid or cefprozil in acute otitis media, and cefalexin in uncomplicated skin infections . Cefdinir given for 5 or 10 days was at least as effective as penicillin V for 10 days in patients with streptococcal pharyngitis/tonsillitis . Cefdinir is usually well tolerated . Diarrhoea was the most common adverse event in trials in all age groups . Although the incidence of diarrhoea in cefdinir recipients was generally higher than in adults and adolescents treated with comparators, discontinuation rates due to adverse events were generally similar for cefdinir and comparator groups.In conclusion, cefdinir is a third-generation cephalosporin with a broad spectrum of antibacterial activity encompassing pathogens that are commonly causative in infections of the respiratory tract or skin and skin structure . Depending on the infection being treated, cefdinir can be administered as a convenient once- or twice-daily 5- or 10-day regimen . Clinical evidence indicates that cefdinir is an effective and generally well tolerated drug with superior taste over comparator antibacterial agents and is therefore a good option for the treatment of adults, adolescents and paediatric patients with specific mild-to-moderate respiratory tract or skin infections, particularly in areas where beta-lactamase-mediated resistance among common community-acquired pathogens is a concern. Pediatr Pulmonol, 2004 Aug, 38(2), 135 - 9 Antigen detection for the diagnosis of pneumonia; Nunes AA et al.; Streptococcus pneumoniae and Haemophilus influenzae type b are the main agents of bacterial community-acquired pneumonia in developing countries, although a definite etiologic diagnosis cannot be established in most cases . This study was carried out to assess the performance of a latex particle agglutination test (LPAT) from a commercial kit (Slidex Meningite Kit trade mark, BioMerieux, France) in diagnosing pneumococcal and H . influenzae type b pneumonia . One hundred and seven children (45 ill subjects and 62 healthy controls) were enrolled . All 45 cases had a presumptive diagnosis of bacterial pneumonia based on clinical (WHO criteria), laboratory (white blood cell count > or = 15.000/mm3, polymorphonuclear leukocytes > or = 70%, bands > or = 500/mm3, and C-reactive protein > or = 40 mg/l), and radiological findings, i.e., two or more positive points in the scoring system described by Khamapirad and Glezen (Semin Respir Infect 1987;2:130-144) . Clinical, laboratory, and radiological assessments were performed in a blinded manner . LPAT was performed in urine samples after concentration through an ethanol-acetone solution . Sensitivity, specificity, and positive and negative predictive values were 77.3% (95% CI, 61.8-88.0%), 90.3% (95% CI, 79.5-96.0%), 85.0% (95% CI, 69.5-93.8%), and 84.8% (95% CI, 73.4-92.1%), respectively . Results suggest that LPAT is a useful diagnostic tool for the etiologic diagnosis of S . pneumoniae and H . influenzae type b pneumonia, especially in the developing world . J Bacteriol, 2004 Jul, 186(13), 4407 - 11 Haemophilus somnus possesses two systems for acquisition of transferrin-bound iron; Ekins A et al.; Haemophilus somnus strain 649 was found to acquire iron from ovine, bovine, and goat transferrins (Tfs) . Expression of Tf receptors, as evaluated by solid-phase binding assays, required the organisms to be grown under iron-restricted conditions in the presence of Tf . Competition binding assays revealed the presence of two distinct Tf-binding receptor systems, one specific for bovine Tf and the other capable of binding all three ruminant Tfs . Affinity isolation procedures using total membranes yielded three putative bovine Tf-binding polypeptides and one putative ovine and goat Tf-binding polypeptide . PCR amplification followed by DNA sequence analyses revealed that H . somnus strain 649 possesses genes that encode a bipartite TbpA-TbpB receptor along with a homolog of the Histophilus ovis single-component TbpA receptor . Expression of TbpB and the single-component TbpA would appear to be subject to a form of phase variation involving homopolymeric nucleotide tracts within the structural genes. J Bacteriol, 2004 Jul, 186(13), 4209 - 17 Evolutionary and functional relationships among the nontypeable Haemophilus influenzae HMW family of adhesins; Buscher AZ et al.; Nontypeable Haemophilus influenzae (NTHi) is a common cause of localized respiratory tract disease and initiates infection by colonizing the nasopharynx . Approximately 75 to 80% of NTHi clinical isolates produce proteins that belong to the HMW family of adhesins, which are believed to facilitate colonization . The prototype HMW adhesins are designated HMW1 and HMW2 and were identified in NTHi strain 12 . HMW1 and HMW2 are 71% identical and 80% similar overall, yet display differing cellular binding specificities . In the present study we set out to define more clearly the relationships between HMW1 and HMW2 and other members of the HMW family of adhesins . PCR analysis of 49 epidemiologically distinct isolates revealed that all strains possessing hmw genes as determined by Southern analysis contain two hmw loci in conserved, unlinked physical locations on the chromosome . Functional analysis of the HMW adhesins produced by three unrelated strains demonstrated that each isolate possesses one protein with HMW1-like adherence properties and another with HMW2-like adherence properties . These findings suggest that the hmw1 and hmw2 loci may have arisen via a gene duplication event in an ancestral strain . In addition, they support the hypothesis that the distinct binding specificities of HMW1 and HMW2 emerged early and have persisted over time, suggesting an ongoing selective advantage. Scand J Infect Dis, 2004, 36(4), 269 - 73 Diagnosis of atypical pathogens in patients hospitalized with community-acquired respiratory infection; Schneeberger PM et al.; The object of our study was to determine the proportion of atypical respiratory pathogens among patients hospitalized with a community-acquired respiratory infection . From September 1997 to May 1999, 159 patients (57% male, median age 55, range 1-88 y) admitted to 3 regional hospitals for a community acquired respiratory infection, were enrolled in the study . Microbiological diagnosis for the atypical pathogens Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila was performed with PCR on a throat swab, sputum and/or broncho alveolar lavage (BAL) . In addition, Legionella species other than L . pneumophila (L . non-pneumophila species) were detected by PCR . Two serum samples were collected and processed for M . pneumoniae and C . pneumoniae serology . In total, 27 patients (17%) were diagnosed with an atypical pathogen . Infection with M . pneumoniae was detected in 19 patients (12%) (PCR positive n = 7), with C . pneumoniae in 5 patients (3%) (PCR positive n = 0) and with L . pneumophila in 4 patients (2.5%) (PCR positive n = 4) . In 54 (34%) patients routine microbiological investigations revealed aetiological agents other than the 3 atypical pathogens, the most frequently diagnosed pathogens being Streptococcus pneumoniae (n = 18), Haemophilus influenzae (n = 17), Gram-negative rods (n = 13), Moraxella catarrhalis (n = 6) and Staphylococcus aureus (n = 6) . More than 1 pathogen was found in 13 patients . Atypical pathogens were found more often in the young age group (0-18 y), in contrast to bacterial pathogens that were found more often in the older age groups (> or = 65 y) . Atypical pathogens were found less often in patients with a clinical presentation of atypical pneumonia . Legionella species other than L . pneumophila were found by PCR in 13 patients (8%), and in 6 patients in combination with another pathogen . An atypical pathogen (M . pneumoniae, C . pneumoniae or L . pneumophila) was found in 17% of the patients hospitalized with a community acquired respiratory infection, predominantly in the young age group . The role of Legionella non-pneumophila species as pathogen in community acquired respiratory infection needs to be determined . The clinical presentation does not predict the type of pathogen found. Int J Antimicrob Agents, 2004 Jun, 23(6), 533 - 46 Antimicrobial selection for community-acquired lower respiratory tract infections in the 21st century: a review of gemifloxacin; Appelbaum PC et al.; Community-acquired lower respiratory tract infections (LRTIs) are more prevalent in the elderly than in children and younger adults and form a significant proportion of all consultations and hospital admissions in this older age group . Furthermore, in a world of increasing life expectancy the trend seems unlikely to be reversed . Antimicrobial treatment of community-acquired pneumonia (CAP) must cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in many circumstances should also cover the intracellular (atypical) pathogens . In contrast, acute exacerbations of chronic bronchitis (AECB) are mainly associated with H . influenzae and S . pneumoniae and not with atypical bacteria: in severe cases, other Gram-negative bacteria may be involved . Frequently in LRTIs, the aetiology of the infection cannot be identified from the laboratory specimens and treatment has to be empirical . In such situations it is important to not only to use an antibiotic that covers all likely organisms, but also one that has good activity against these organisms given the local resistance patterns . Gemifloxacin is a new quinolone antibiotic that targets pneumococcal DNA gyrase and topoisomerase IV and is highly active against S . pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant strains, as well as H . influenzae and the atypical pathogens . In clinical trials in CAP and AECB, gemifloxacin has been shown to be as effective a range of comparators and demonstrated an adverse event profile that was in line with the comparator agents . In one long-term study in AECB significantly more patients receiving gemifloxacin than clarithromycin remained free of recurrence after 26 weeks . The improved potency, broad spectrum of activity and proven clinical and bacteriological efficacy and safety profile should make it a useful agent in the 21st century battle against community-acquired LRTIs . Clin Microbiol Infect, 2004 Jun, 10(6), 521 - 6 Antimicrobial susceptibility to levofloxacin and other antibacterial agents among common respiratory pathogens-a Brazilian perspective from the GLOBAL Surveillance Initiative 2001-2002; Mendes C et al.; The GLOBAL (Global Landscape On Bactericidal Activity of Levofloxacin) Surveillance programme monitored antimicrobial susceptibility patterns of the key respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis collected in Brazil during 1997-1998, 1999-2000 and 2001-2002 . Penicillin and azithromycin resistance among S . pneumoniae strains increased from 1997-1998, reaching 7.9% and 9.5%, respectively, in 2001-2002 . Although decreasing by 4.9% since the previous study, trimethoprim-sulphamethoxazole resistance remained high at 33.7% . Concurrent resistance to penicillin, azithromycin and trimethoprim-sulphamethoxazole was seen in 2.9% of the S . pneumoniae isolates collected . Levofloxacin remained extremely active against S . pneumoniae, with 0.3% resistance reported in 1997-1998 and 0% resistance in 1999-2000 and 2001-2002 . beta-Lactamase production in H . influenzae was > 10% in all three studies, with correspondingly high rates of ampicillin resistance . Trimethoprim-sulphamethoxazole was the least active agent tested against H . influenzae, with resistance rates of > 40% recorded in all three studies . All H . influenzae isolates were susceptible to cefuroxime, ceftriaxone, azithromycin and levofloxacin . Of the M . catarrhalis isolates, 98.0% in 1997-1998, 98.0% in 1999-2000 and 81.8% in 2001-2002 were beta-lactamase-positive . The continued high prevalence of antimicrobial resistance in Brazil underscores the importance of current surveillance initiatives . Levofloxacin, a fluoroquinolone prescribed widely for respiratory tract infections, continued to show potent activity against key respiratory pathogens. J Antimicrob Chemother, 2004 Jul, 54(1), 225 - 8 Epub 2004 Jun 09. Ultrastructure of Streptococcus pneumoniae after exposure to xylitol; Tapiainen T et al.; OBJECTIVES: Xylitol is a sugar alcohol which reduces the growth of Streptococcus pneumoniae and the adherence of pneumococci and Haemophilus influenzae to nasopharyngeal cells . Xylitol prevents acute otitis media but does not decrease nasopharyngeal carriage of pneumococci . We hypothesized that xylitol could affect the surface structures of viable pneumococci, which would further explain the mechanism of action of xylitol in preventing acute otitis media . METHODS: We exposed five strains of pneumococci to 0.5%-5% xylitol, 5% glucose, 5% fructose and 5% sorbitol or control medium (brain heart infusion) for 0.5-2 h and examined the ultrastructure of bacteria by electron microscopy . RESULTS: The cell wall of pneumococci became more diffuse, the polysaccharide capsule became ragged and the proportion of damaged pneumococci increased after exposure to xylitol for 2 h, but not after exposure to other sugars or control medium . The phenotype of all pneumococcal strains was opaque before xylitol exposure and became almost transparent both in xylitol and in control medium during the experiment . CONCLUSIONS: This study demonstrates further that xylitol has a harmful effect on pneumococci . The observed changes in the polysaccharide capsule and the cell wall of pneumococci could affect the adherence and virulence of pneumococci, explaining the good clinical efficacy of xylitol in the prevention of acute otitis media. Clin Ther, 2004 Apr, 26(4), 522 - 30 Comparative in vitro activity of telithromycin and beta-lactam antimicrobials against community-acquired bacterial respiratory tract pathogens in the United States: findings from the PROTEKT US study, 2000-2001; Stratton CW et al.; BACKGROUND: Telithromycin is a new ketolide antimicrobial that was developed to provide good activity against resistant respiratory tract pathogens . PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) is a multicenter in vitro surveillance study that was initiated in 2000 to chart the emergence and spread of antimicrobial-resistant pathogens in patients with community-acquired respiratory tract infections (CARTIs) . OBJECTIVE: This article reports first-year results from PROTEKT US pertaining to the comparative in vitro activity of telithromycin and beta-lactam antimicrobials against community-acquired bacterial respiratory tract pathogens . METHODS: Data were compiled on the comparative in vitro activity of telithromycin and beta-lactams against Streptococcus pneumoniae (10,103 isolates), Streptococcus pyogenes (3918 isolates), and Haemophilus influenzae (2706 isolates) . Minimum inhibitory concentrations (MICs) and susceptibilities were determined according to National Committee for Clinical Laboratory Standards methods . RESULTS: In total, 38.8% (3920/10,103) of pneumococcal isolates were not susceptible to penicillin (12.5% {1266} intermediate {MIC, > or =0.12-1.0 mg/dL}, 26.3% {2654} resistant {MIC, > or =2 mg/dL}) . Telithromycin was highly active against S pneumoniae (MIC required to inhibit 90% of isolates {MIC(90)}, 0.5 mg/L), with 99.6% (10,062/10,103) of isolates fully susceptible (MIC, < or =1 mg/L) . Based on MIC(90)s, the rank order of antimicrobial activity was telithromycin (0.5 mg/L), followed by amoxicillin/clavulanate (2 mg/L), penicillin (4 mg/L), and cefuroxime (8 mg/L) . Telithromycin retained high activity (MIC(90), 1 mg/L) against penicillin-resistant penumococci that showed high levels of coresistance to beta-lactams . All isolates of S pyogenes were fully susceptible to the beta-lactams tested . Beta-lactamase production was common among H influenzae isolates (28.3% {765/2706}) . Telithromycin was active against H influenzae (MIC(90), 4 mg/L), irrespective of beta-lactamase production . Conclusion: Overall, these findings from the first year of PROTEKT US support the potential value of telithromycin in the treatment of CARTIs. Ann Pharmacother, 2004 Jul-Aug, 38(7-8), 1226 - 35 Epub 2004 Jun 08. Gemifloxacin: a new fluoroquinolone approved for treatment of respiratory infections; Yoo BK et al.; OBJECTIVE: To evaluate the microbiology, pharmacokinetic parameters, drug interactions, and results of the available clinical trials of gemifloxacin for the treatment of community-acquired pneumonia (CAP) and acute exacerbation of chronic bronchitis (AECB) . DATA SOURCES: MEDLINE (1966-September 2003) was searched for primary and review articles . Data from the manufacturer were also included . Key words included adverse effects, clinical trials, drug interactions, gemifloxacin, and pharmacokinetic parameters . STUDY SELECTION AND DATA EXTRACTION: All articles and product labeling concerning gemifloxacin, a fluoroquinolone antibiotic recently approved by the Food and Drug Administration for treatment of CAP and AECB, were included for review . DATA SYNTHESIS: Compared with currently available fluoroquinolones, gemifloxacin demonstrated improved in vitro activity against Streptococcus pneumoniae (minimum inhibitory concentration for 90% eradication 0.03 microg/mL) and similar activity against gram-negative respiratory pathogens (Haemophilus influenzae, Moraxella catarrhalis) and atypical pathogens such as Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae . Gemifloxacin, consistent with other available fluoroquinolones, has insufficient activity against methicillin-resistant Staphylococcus aureus to allow clinical use for such infections . Gemifloxacin has adequate bioavailability and a favorable drug interaction profile . Gemifloxacin was comparable to commonly employed nonfluoroquinolone regimens for treatment of CAP and AECB, although the studies were designed to demonstrate equivalence . Gemifloxacin once daily for 5-7 days was well tolerated in controlled and uncontrolled clinical studies . Available clinical data, however, are insufficient to draw clinical or toxicologic distinctions between gemifloxacin and other fluoroquinolones . CONCLUSIONS: Gemifloxacin may be a suitable choice for empiric treatment of CAP or AECB . However, due to the significant history of fluoroquinolone-induced hepatic failure and dermatologic complications, the use of this drug should be closely monitored. Int J STD AIDS, 2004 Jun, 15(6), 367 - 70 Genital syndromes and syndromic management of vaginal discharge in a community setting; George R et al.; The objective of the study was to determine the community prevalence of genital syndromes in women and evaluate the syndromic management of vaginal discharge in this setting . A representative sample for the state of Tamilnadu was chosen using probability proportional to size cluster technique . Thirty clusters were selected from three districts . Demographic, sexual behaviour, risk factors, clinical and laboratory data were collected from the selected population using a structured questionnaire . Direct smear examination for Trichomonas vaginalis, culture for Neisseria gonorrhoeae and Haemophilus ducreyi, serological tests for syphilis (RPR and TPHA), hepatitis B (Hbs Ag ELISA), IgM and IgG antibodies to HSV2 (Novum diagnostics, Germany) and PCR test for detection of C . trachomatis from urine were done . There were 1157 women in the selected population . On examination, vaginal discharge was the most common genital syndrome (38.4%) . The sensitivity, specificity, positive and negative predictive value of vaginal discharge as a marker for STD in women was found to be 43.3%, 61.6%, 10.7% and 91.1%, respectively . We concluded that treatment on the basis of syndromic management would result in over-treatment of 90% of women with vaginal discharge. AIDS Res Hum Retroviruses, 2004 May, 20(5), 493 - 6 Haemophilus influenzae type b immunization in adults infected with the human immunodeficiency virus; De Sousa dos Santos S et al.; The purpose of this study was to assess the influence of Haemophilus influenzae type b conjugate vaccine on HIV-1 RNA level, CD4 count, and anti-Hib polysaccharide (PRP) antibody concentration . Eighty HIV-infected adults were randomized to receive Hib conjugate vaccine or not . Twenty HIV-seronegative controls were also vaccinated . Blood samples were taken before and after vaccination, with a follow-up period of 6 months . HIV infection markers and anti-PRP antibodies were monitored . There was no change in either HIV-1 viremia or CD4 count after vaccination . Immunization immunogenicity was superior in HIV-uninfected than in HIV-infected individuals (p < 0.01) . Hib vaccination was safe but induced suboptimal antibody response in HIV-infected adults. Pediatr Dent, 2004 May-Jun, 26(3), 283 - 8 Comparison of oral findings in special needs children with and without gastrostomy; Jawadi AH et al.; PURPOSE: The objective of this study was to compare aspiration pneumonia (AP)-associated microflora, calculus, and oral hygiene/care seeking behaviors in special health care needs children (SC) with gastrostomy (GT) and without . METHODS: Twenty-seven GT SC, ages 3 to 12 years old and matched for age and gender with 27 non-GT SC, were examined by 2 trained investigators who recorded calculus and gingival inflammation and reconciled differences . Plaque was obtained using preweighed dry paper points and saliva sampled using sterile pipettes and cultured using standard bioassay procedures in a hospital laboratory . Parent/caretakers completed a medical and oral health questionnaire . RESULTS: No significant differences were noted for age, gender, weight, primary diagnosis, vomiting, constipation, or swallowing disorder, but GT children received 4 medications vs 1 for non-GT and were significantly more likely to have had AP, need special feeding, and drool (P < or = .05) . Oral health measures were not significantly different for brushing frequency, dentifrice use, brushing problems, frequency of dental care, or gingival inflammation, but GT patients had significantly more plaque and calculus . GT patients had significantly more Haemophilus influenzae, with trends toward more gram negative enteric rods, pseudomonas, and Streptococcus pneumoniae and higher concentrations in several GT-patients and little or none in non-GT patients . GT SC had significantly less beta-streptococci than non-GT patients (P < or = .05) . CONCLUSIONS: GT SC had significantly more of 1 AP-associated organism than non-GT SC and significantly more calculus and plaque, in spite of similar care seeking and hygiene behaviors. Epidemiol Mikrobiol Imunol, 2004, 53(2), 74 - 7 {Characterization of Haemophilus influenzae strains using multilocus sequencing}; Krizova P et al.; First results of multilocus sequence typing (MLST) of Haemophilus influenzae strains are presented . MLST of 28 H . influenzae strains isolated from patients with invasive diseases in the Czech Republic is indicative of clonal homogeneity of these strains: 22 out of 26 H . influenzae b strains tested were of the same sequence type, ST-6 . Four strains were of two sequence types newly described in this study: ST-83 (3 strains) and ST-84 (1 strain) . Two nontypeable H . influenzae strains were assigned to sequence types other than ST-6: ST-3 and ST-85 newly described in this study . First MLST results show ST-6 to be typical of H . influenzae b isolated from patients with invasive diseases in the Czech Republic . The sequence types newly described in this study, i.e . ST-83, ST-84 and ST-85, were submitted to the worldwide H . influenzae MLST database . Onderstepoort J Vet Res, 2004 Mar, 71(1), 53 - 8 Evidence of possible evasion of protective immunity by NAD-independent isolates of Haemophilus paragallinarum in poultry; Bragg RR; An indication of the ability of NAD-independent variants of Haemophilus paragallinarum to evade the immune system has been obtained from data obtained from several experiments . Firstly, it was noted that there was a difference in the serovar distribution between the NAD-dependent isolates in the 1990s and the NAD-independent isolates, as there was a significant decrease in the incidence of serogroup A NAD-dependent isolates . This can possibly be attributed to the extensive use of vaccines . On the other hand, most of the earlier NAD-independent isolates were serovar A . This is a possible indication of evasion of the protective immunity by the NAD-independent isolates . Further evidence of possible evasion of the protective immunity was obtained from results obtained when different isolates, both NAD dependent and NAD independent, were tested with a panel of monocional antibodies (Mabs) . The V1 Mab reaction pattern was only seen in the reference strain 0083 among all of the NAD-dependent isolates tested in South Africa . This Mab was, however, found to react with some of the NAD-independent isolates . Furthermore, the isolation of NAD-dependent isolates in Australia which react with the V1 Mab also suggest possible evasion of the protective immunity by the NAD-independent isolates as no vaccines containing strain 0083 are used in Australia . In order to investigate the hypothesis of immune-evasion by NAD-independent H . paragallinarum, vaccinated and unvaccinated chickens were challenged with a NAD-independent serogroup C isolate . As a control, chickens were also challenged with NAD-dependent H . paragallinarum of the same serogroup . The results obtained indicate that there is no significnat difference in the disease profiles obtained in vaccinated and unvaccinated chickens challenged with the NAD-independent isolate, thus providing further evidence of evasion of the productivity immunity by the NAD-independent isolates . The ability of the NAD-independent isolates to evade the immune system suggests that a different vaccination strategy, or alternative control methods may be needed for the control of IC caused by these isolates. Onderstepoort J Vet Res, 2004 Mar, 71(1), 1 - 8 Limitation of the spread and impact of infectious coryza through the use of a continuous disinfection programme; Bragg RR; The effect of a continuous disinfection programme, using the non-toxic disinfectant Virukill, in layers, on the spread and impact of infectious coryza, caused by Haemophilus paragallinarum was evaluated . In this experiment, both unvaccinated layers and layers vaccinated against infectious coryza were used . Duplicate smaller groups of vaccinated and unvaccinated chickens were challenged with different serovars of both NAD-dependent as well as NAD-independent isolates of Haemophilus paragallinarum . One group of chickens challenged with each of the different becterial serovars was treated with the continuous disinfection programme, while the other group remained as the untreated controls . The clinical signs of infectious coryza were evaluated over a period of 20 days in each group . The egg production over this period was also evaluated . It was found in all experimental challenges, that the severity of the symptoms was reduced in the birds receiving the continuous disinfection programme . The drop in egg production was also found to be less severe in the treated groups when compared to the untreated control groups . The duration of infection was found to be either unchanged, or shorter in the birds treated with the continuous disinfection programme . In none of the experimental challenges was the duration or expression of clinical signs of IC increased due to the continuous disinfection programme. Respirology, 2004 Jun, 9(2), 278 - 82 Clinical features of Q fever pneumonia; Okimoto N et al.; The aim of the study was to assess the clinical features of Q fever pneumonia in Japan . Four cases of Q fever pneumonia (a female aged 21 and males aged 53, 74 and 87 years) who were diagnosed using the PanBio ELISA test kit, were assessed and their clinical features are described . The frequency of Q fever pneumonia among our cases of community-acquired pneumonia was 1.4% (4/284) . A 21-year-old female had a typical case of the disease with (i) a history of owning a cat, (ii) onset with fever and dry cough, (iii) multiple soft infiltrative shadows on CXR, (iv) a normal white blood cell count, and (v) good response to clarithromycin . The pneumonias in the other three cases were considered mixed infections with bacteria such as Streptococcus pneumoniae and Haemophilus influenzae . Their clinical features included the following: (i) an elderly person with an underlying disease, (ii) onset with fever and purulent sputum, (iii) coarse crackles on auscultation, (iv) infiltrative shadows and pleural effusion on CXR, (v) increased white blood cells with elevated BUN and hyponatraemia, and (vi) modest responses to combined therapy with carbapenem and minocycline . Our observations suggest that two types of pneumonia caused by Coxiella burnetti exist; one with the usual features of atypical pneumonia, and the other presenting with the clinical features of bacterial pneumonia in the elderly due to mixed bacterial infection. Clin Lab Med, 2004 Jun, 24(2), 531 - 51 Evolution of amoxicillin/clavulanate in the treatment of adults with acute bacterial rhinosinusitis and community-acquired pneumonia in response to antimicrobial-resistance patterns; File TM Jr et al.; Current treatment guidelines for community-acquired respiratory tract infections no longer depend solely on the characteristics of the patient and the clinical syndrome, but on those of the offending pathogen, including presence and level of antimicrobial resistance . The most common respiratory tract pathogens known to cause acute bacterial rhinosinusitis (ABRS) and community-acquired pneumonia (CAP) include Streptococcus pneumoniae and Haemophilus influenzae . The prevalence of antimicrobial resistance, especially b-lactum and macrolide resistance, among S pneumoniae and H influenzae has increased dramatically during the past 2 decades, diminishing the activity of many older antimicrobials against resistant organisms . A pharmacokinetically enhanced formulation of amoxicillin/clavulanate has been developed to fulfill the need for an oral b-lactam antimicrobial that achieves a greater time that the serum drug concentration exceeds the minimum inhibitory concentration (T > MIC) of antimicrobials against pathogens than conventional formulations to improve activity against S pneumoniae with reduced susceptibility to penicillin . The b-lactamase inhibitor clavulanate allows for coverage of b-lactamase-producing pathogens, such as H influenzae and M catarrhalis . This article reviews the rationale for, and evolution of, oral amoxicillin clavulanate for ABRS and CAP Clin Lab Med, 2004 Jun, 24(2), 503 - 30 Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to 17 oral antimicrobial agents based on pharmacodynamic parameters: 1998-2001 U S Surveillance Study; Jacobs MR et al.; Pharmacokinetic/pharmacodynamic parameters were used to interpret susceptibility data for the oral agents tested in a clinically meaningful way . Among S pneumoniae isolates, >99% were susceptible to respiratory fluoroquinolones, 91.6% to amoxicillin, 92.1% to amoxicillin/clavulanic acid (95.2% at the extended-release formulation breakpoint), 90.6% to clindamycin, 80.4% to doxycycline, 71.0% to azithromycin, 72.3% to clarithromycin, 71.8% to cefprozil and cefdinir, 72.6% to cefuroxime axetil, 66.3% to cexime, 63.7% to trimethoprim/sulfamethoxazole, and 19.7% to cefaclor . Among H influenzae isolates, 28.6% were b-lactamase positive, but virtually all were susceptible to amoxicillin/clavulanic acid (98.3%, with 99.8% at the extended-release formulation breakpoint), cexime (100%), and uoroquinolones (99.8%), whereas 93.5% were susceptible to cefdinir, 82.8% to cefuroxime axetil, 78.1% to trimethoprim/sulfamethoxazole, 70.2% to amoxicillin, 25.1% to doxycycline, 23.2% to cefprozil, and 5% to cefaclor, azithromycin and clarithromycin . Most isolates of M catarrhalis were resistant to amoxicillin, cefaclor, cefprozil, and trimethoprim/sulfamethoxazole . Thus significant b-lactam and macrolide/azalide resistance in Streptococcus pneumoniae and b-lactamase production and trimethoprim/sulfamethoxazole resistance in untypeable Haemophilus influenzae are still present . The results of this study should therefore be applied to clinical practice based on the clinical presentation of the patient, the probability of the patient's having a bacterial rather than a viral infection, the natural history of the disease, the potential of pathogens to be susceptible to various oral antimicrobial agents, the potential for cross-resistance between agents with S pneumoniae, and the potential for pathogens to develop further resistance . Antibiotics should be used judiciously to maintain remaining activity and chosen carefully based on activity determined by pharmacokinetic/pharmacodynamic-based breakpoints to avoid these bacteria developing further resistance, particularly to fluoroquinolones. Clin Lab Med, 2004 Jun, 24(2), 455 - 75 Macrolide resistance in Streptococci and Haemophilus influenzae; Bozdogan B et al.; Antimicrobial resistance is a growing problem among pathogens from respiratory tract infections . b-Lactam resistance rates are escalating among Streptococcus pneumoniae and Haemophilus influenzae . Macrolides are increasingly used for the treatment of respiratory tract infections, but their utility is compromised by intrinsic and acquired resistance . This article analyses macrolide-resistance mechanisms and their worldwide distributions in S pneumoniae, S pyogenes, and H influenzae. Rev Prat, 2004 Mar 15, 54(5), 526 - 31 {Vaccines pharmacovigilance}; Autret-Leca E et al.; The pharmacovigilance of vaccines has the particularity of concerning medications with a preventative target, used in healthy subjects, who are often young . Their individual benefit is deferred and unknown, whereas their risk is immediate . Certain undesirable effects are linked to the antigen of live attenuated vaccines (post-MMR lymphocytic meningitis) . Other non-specific effects are linked to other different components of the vaccines (macrophage and aluminium myofasciitis) . Undesirable events susceptible to being due to the vaccination are identified and managed according to standardised procedures of pharmacovigilance, that is to say, based on "spontaneous notification", generation of an alert, confirmed or not by studies of pharmaco-epidemiology . The studies of pharmaco-epidemiology: have made evident oedematous reactions with cyanosis or purpura, with the vaccines containing the Haemophilus b valence, and the absence of an association with sudden death of the newborn; have excluded the existence of an elevated risk of demyelinisation or auto-immune disease associated with vaccination against hepatitis B, without being able to exclude a slight risk; go against the finding of an association between Crohn's disease and/or autisim and the MMR vaccination . Only their frequently encountered undesirable effects are well identified at the moment of commercialisation . Post-marketing surveillance of vaccines (declaration to the regional pharmacovigilance centres) allow the detection of possible rare and serious effects and the evaluation of the real vaccination risk . Thus it must be intensive and systematic. Semin Pediatr Infect Dis, 2004 Jan, 15(1), 5 - 20 Antimicrobial resistance among pediatric respiratory tract infections: clinical challenges; Jacobs MR et al.; Considerable development of antimicrobial resistance has occurred in the major pediatric bacterial pathogens, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis . However, most of the respiratory infections that children suffer are viral and self-limiting, and only a small percentage of them will develop secondary bacterial infections with the pathogens listed . The challenge for rational antibiotic use is to determine which patients can be treated conservatively and which require antimicrobial intervention to avoid prolonged discomfort or development of permanent sequelae . The basis for rational use of antibiotic in the era of resistance in these major pathogens is to avoid overuse of antimicrobial agents, tailor treatment to identified pathogens as much as possible, and base empiric treatment on the disease being treated and the susceptibility of the probable pathogens at breakpoints based on pharmacokinetic and pharmacodynamic parameters . With appropriate dosing regimens based on these parameters and despite development of resistance, amoxicillin is still one of the most active oral agents against S . pneumoniae and non-beta-lactamase producing strains of H . influenzae, whereas amoxicillin-clavulanate is active against beta-lactamase-producing strains of H . influenzae and M . catarrhalis . Parenteral ceftriaxone and oral and parenteral fluoroquinolones are active against all 3 species, but fluoroquinolones should be used with utmost caution when all other options have been considered because of concerns about toxicity and development of resistance . Introduction of a 7-valent conjugate pneumococcal vaccine in the United States in 2000 reduced the prevalence of invasive pneumococcal disease in children younger than 2 years old, but, as of 2001, had not had a major impact on decreasing antimicrobial resistance. Rev Argent Microbiol, 2004 Jan-Mar, 36(1), 20 - 3 {Isolation of Haemophilus influenzae serotypes from deep sites in sick children}; Gatti BM et al.; Haemophilus influenzae (Hi) is the causative agent of several human diseases such as sepsis, meningitis, celulitis, and osteoarthritis . We investigated the isolation of Hi serotypes from sterile sites in sick children . One hundred and seventy nine strains from 146 patients were studied, period 1996-2002, at the Microbiology Laboratory, Hospital de Ninos Superiora Sor Maria Ludovica, Argentina . The serotype distribution was:1 a, 112 b,1 c,1 d, 4 e, 3 f y 24 no typable . Since the beginning of universal Hi b vaccination in 1998, we have observed the fast decrease of serotype b and a relative increase of other serotypes. Pediatrics, 2004 Jun, 113(6 Suppl), 1959 - 64 Insurance status and vaccination coverage among US preschool children; Santoli JM et al.; BACKGROUND: Insurance status has been shown to have an impact on children's use of preventive and acute health services . The objective of this study was to determine the relationship between insurance status and vaccination coverage among US preschool children aged 19 to 35 months . METHODS: We linked data from 2 national telephone surveys, the National Immunization Survey and the National Survey of Early Childhood Health, conducted during the first half of 2000 . Children were considered up to date (UTD) when they had received at least 4 diphtheria-tetanus-acellular pertussis/diphtheria-tetanus-pertussis vaccines, 3 poliovirus vaccines, 1 MMR vaccine, 3 Haemophilus influenza vaccines, and 3 hepatitis B vaccines at the time the interview was conducted . RESULTS: Among the 735 children in our study sample, 72% were UTD . The vast majority (94%) reported some type of health insurance at the time of the survey . Children with private insurance were more likely to be UTD (80%) than those with public insurance (56%) or no insurance (64%) . In a multivariate analysis that controlled for child's race/ethnicity; household income; maternal age/marital status/educational level; location of usual care; and Special Supplemental Nutrition Program for Women, Infants, and Children participation, insurance was no longer an independent predictor of vaccination . CONCLUSIONS: The disparity in vaccination coverage among publicly, privately, and uninsured children is dramatic, underscoring its importance as a marker for underimmunization, despite the multivariate findings . The Vaccines for Children Program, a partnership between public health and vaccination providers who serve uninsured children and those enrolled in Medicaid, is well suited to target and improve vaccination coverage among these vulnerable children. JAMA, 2004 Jun 2, 291(21), 2555 - 62 Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted infections and HIV-1 infection in Kenyan sex workers: a randomized controlled trial; Kaul R et al.; CONTEXT: Sexually transmitted infections (STIs) are common in female sex workers (FSWs) and may enhance susceptibility to infection with human immunodeficiency virus type 1 (HIV-1) . OBJECTIVE: To examine regular antibiotic prophylaxis in FSWs as a strategy for reducing the incidence of bacterial STIs and HIV-1 . DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted between 1998-2002 among FSWs in an urban slum area of Nairobi, Kenya . Of 890 FSWs screened, 466 who were seronegative for HIV-1 infection were enrolled and randomly assigned to receive azithromycin (n = 230) or placebo (n = 236) . Groups were well matched at baseline for sexual risk taking and STI rates . INTERVENTION: Monthly oral administration of 1 g of azithromycin or identical placebo, as directly observed therapy . All participants were provided with free condoms, risk-reduction counseling, and STI case management . MAIN OUTCOME MEASURES: The primary study end point was incidence of HIV-1 infection . Secondary end points were the incidence of STIs due to Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus ducreyi, as well as bacterial vaginosis . Analysis of herpes simplex virus type 2 (HSV-2) infection was performed post hoc . RESULTS: Seventy-three percent of participants (n = 341) were followed up for 2 or more years or until they reached an administrative trial end point . Incidence of HIV-1 did not differ between treatment and placebo groups (4% {19 cases per 473 person-years of follow-up} vs 3.2% {16 cases per 495 person-years of follow-up} rate ratio {RR}, 1.2; 95% CI, 0.6-2.5) . Incident HIV-1 infection was associated with preceding infection with N gonorrhoeae (rate ratio {RR}, 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0; 95% CI, 1.1-8.9) . There was a reduced incidence in the treatment group of infection with N gonorrhoeae (RR, 0.46; 95% CI, 0.31-0.68), C trachomatis (RR, 0.38; 95% CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI, 0.40-0.78) . The seroprevalence of HSV-2 infection at enrollment was 72.7%, and HSV-2 infection at baseline was independently associated with HIV-1 acquisition (RR, 6.3; 95% CI, 1.5-27.1) . CONCLUSIONS: Despite an association between bacterial STIs and acquisition of HIV-1 infection, the addition of monthly azithromycin prophylaxis to established HIV-1 risk reduction strategies substantially reduced the incidence of STIs but did not reduce the incidence of HIV-1 . Prevalent HSV-2 infection may have been an important cofactor in acquisition of HIV-1. Vet Microbiol, 2004 Jun 21, 101(2), 143 - 6 Antimicrobial susceptibility of Haemophilus parasuis and Histophilus somni from pigs and cattle in Denmark; Aarestrup FM et al.; A total of 52 Haemophilus parasuis and 80 Histophilus somni isolates were tested for antimicrobial susceptibility by MIC-determinations . None of the isolates were resistant to ampicillin, ceftiofur, ciprofloxacin, erythromycin, florphenicol, penicillin, spectinomycin, tetracycline, tiamulin, or tilmicosin . Two H . parasuis isolates were resistant to trimethoprim + sulfamethoxazole . Six H . parasuis isolates had reduced susceptibility (0.06-0.5 microg/ml) to ciprofloxacin and 10 reduced susceptibility to TMP + sulfamethoxazole (1-2 microg/ml) . This study showed that Danish isolates of H . parasuis and H . somni in general are fully susceptible to antimicrobial agents currently used for treatment of infections with these pathogens . Am J Physiol Lung Cell Mol Physiol, 2004 Sep, 287(3), L598 - 607 Epub 2004 May 28. Modulation of airway inflammation and bacterial clearance by epithelial cell ICAM-1; Humlicek AL et al.; Many cell types in the airway express the adhesive glycoprotein for leukocytes intercellular adhesion molecule-1 (ICAM-1) constitutively and/or in response to inflammatory stimuli . In this study, we identified functions of ICAM-1 on airway epithelial cells in defense against infection with Haemophilus influenzae . Initial experiments using a mouse model of airway infection in which the bacterial inoculum was mixed with agar beads that localize inflammation in airways demonstrated that ICAM-1 expression was required for efficient clearance of H . influenzae . Airway epithelial cell ICAM-1 expression required few or no leukocytes, suggesting that epithelial cells could be activated directly by interaction with bacteria . Specific inhibition of ICAM-1 function on epithelial cells by orotracheal injection of blocking antibodies resulted in decreased leukocyte recruitment and H . influenzae clearance in the airway . Inhibition of endothelial cell ICAM-1 resulted in a similar decrease in leukocyte recruitment but did not affect bacterial clearance, indicating that epithelial cell ICAM-1 had an additional contribution to airway defense independent of effects on leukocyte migration . To assess this possibility, we used an in vitro model of neutrophil phagocytosis of bacteria and observed significantly greater engulfment of bacteria by neutrophils adherent to epithelial cells expressing ICAM-1 compared with nonadherent neutrophils . Furthermore, bacterial phagocytosis and killing by neutrophils after interaction with epithelial cells were decreased when a blocking antibody inhibited ICAM-1 function . The results indicate that epithelial cell ICAM-1 participates in neutrophil recruitment into the airway, but its most important role in clearance of H . influenzae may be assistance with neutrophil-dependent bacterial killing. Int J Antimicrob Agents, 2004 Mar, 23(3), 296 - 9 Antimicrobial susceptibility of Haemophilus influenzae, Haemophilus parainfluenzae and Moraxella catarrhalis isolated from adult patients with respiratory tract infections in four southern European countries . The ARISE project; Soriano F et al.; Over a 7-month period in 2000-2001, 1213 Haemophilus influenzae, 112 Haemophilus parainfluenzae and 142 Moraxella catarrhalis isolates were recovered from adult patients with respiratory tract infections . Patients were from four southern European countries (Spain, Italy, Portugal and Greece) . The antimicrobial susceptibility of the isolates to 11 antibiotics was determined in a central laboratory . The most active drugs on the basis of MICs were levofloxacin, cefditoren, cefotaxime, cefpodoxime and amoxicillin/clavulanate . MICs > or = 2 mg/l for amoxicillin were found in 19.5, 28.6, and 75.4% of H . influenzae, H . parainfluenzae and M . catarrhalis isolates, respectively . Isolates of H . influenzae and H . parainfluenzae with reduced susceptibility or that were fully resistant to amoxicillin/clavulanate, cefuroxime and clarithromycin were detected (0.2-1.8%) as well as M . catarrhalis resistant to clarithromycin (0.7%) . Regular surveys of resistance patterns for antimicrobial agents are necessary. Int J Antimicrob Agents, 2004 Mar, 23(3), 218 - 25 PK-PD modelling of the effect of cefaclor on four different bacterial strains; de la Pena A et al.; The effect of cefaclor against relevant bacterial strains was studied by employing a combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) approach . For this purpose selected isolates of Escherichia coli, Moraxella catarrhalis, Haemophilus influenzae and Streptococcus pneumoniae were exposed in vitro to the interstitial cefaclor profile obtained in vivo in the interstitial space fluid of human tissue after administration of commonly used doses of cefaclor and the change in the number of colony forming units per millilitre (CFU/ml) versus time was monitored . Fitting of the data using a modified E(max)-model resulted in a set of mean pharmacodynamic parameters (k0, k(max), EC50) for each bacterial strain . The parameters derived from these experiments were used in a computer-simulation of the antibacterial effects for different dosing regimens and formulations of cefaclor, notably an immediate (IR) and a modified (MR) release formulation . Dosage regimens were compared using the ratio between the number of bacteria remaining after 24 h of a given treatment (N24h) . The results indicate that the number of bacteria of all investigated strains killed per day is equivalent when the same daily dose is administered twice a day with the MR dosage form than when given three times a day with the IR dosage form, in spite of the fact that the MR dosage form has approximately 20% lower bioavailability . Best results were obtained with the three-times a day regimen of the MR formulation . In conclusion, the present in vivo-PK/in vitro-PD simulations of the antimicrobial effects of cefaclor indicate that a twice-daily treatment with a MR formulation may offer a convenient and safe alternative to the conventional tid treatment. Nature, 2004 May 27, 429(6990), 429 - 33 Assembly and function of a bacterial genotoxin; Nesic D et al.; The tripartite cytolethal distending toxin (CDT) induces cell cycle arrest and apoptosis in eukaryotic cells . The subunits CdtA and CdtC associate with the nuclease CdtB to form a holotoxin that translocates CdtB into the host cell, where it acts as a genotoxin by creating DNA lesions . Here we show that the crystal structure of the holotoxin from Haemophilus ducreyi reveals that CDT consists of an enzyme of the DNase-I family, bound to two ricin-like lectin domains . CdtA, CdtB and CdtC form a ternary complex with three interdependent molecular interfaces, characterized by globular, as well as extensive non-globular, interactions . The lectin subunits form a deeply grooved, highly aromatic surface that we show to be critical for toxicity . The holotoxin possesses a steric block of the CdtB active site by means of a non-globular extension of the CdtC subunit, and we identify putative DNA binding residues in CdtB that are essential for toxin activity. J Clin Immunol, 2004 Jul, 24(4), 354 - 60 Antibody levels after regular childhood vaccinations in the immunological screening of children with recurrent otitis media; Wiertsema SP et al.; Recurrent otitis media may be related to defects in specific antibody production, as suggested previously . This might be reflected in lower antibody responses to vaccinations administered in the context of the national childhood vaccination program in children suffering from recurrent otitis media . In a cross-sectional study we determined the levels of antidiphtheria, antitetanus, anti- Haemophilus influenzae type b (anti-Hib) and antimeasles antibodies in sera of 163 children with two or more episodes of acute otitis media per year and in 143 children with repeated periods of persistent otitis media with effusion each lasting at least 3 months . The control group consisted of 521 age-matched healthy children, who were free of recurrent respiratory tract infections . Children with recurrent acute otitis media, including highly otitis-prone children, showed higher antidiphtheria and antitetanus antibody titers compared to