Keith P. Klugman

Immunogenicity, efficacy and serological correlate of protection of Salmonella typhi Vi capsular polysaccharide vaccine three years after immunization

The protective efficacy and immunogenicity of Vi capsular polysaccharide vaccine against typhoid fever was measured 3 years after its administration in a double-blind randomized trial. Vaccine efficacy was not significantly different during each year of the trial and was 55% (95% CI: 30-71%) over the 3 year period. In a case-control study at 3 years after vaccination, recipients of Vi had higher levels of Vi antibodies than controls, as measured by radio-immunoassay (GMT 1.28 vs 0.76 microgram ml-1, P = 0.0004) and by passive haemagglutination assay (GMT 10.46 vs 3.52, P = 0.0001). The serological correlate of protection has been estimated using the relative risks of typhoid fever in the 2 groups and the relative ratio of antibody levels. The estimated protective level is 1 microgram ml-1 suggesting that at a mean age of 9 years, 64% of vaccinates and 40% of controls had protective antibody against typhoid fever in this endemic area.

Nasopharyngeal carriage and antimicrobial resistance in isolates of Streptococcus pneumoniae and Haemophilus influenzae type b in children under 5 years of age in Botswana

OBJECTIVESnA prospective survey was conducted to determine the prevalence of asymptomatic nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae type b in children under 5 years of age in Botswana and to determine the antibiotic resistance patterns of these organisms to commonly used antimicrobial agents.nnnMETHODSnChildren 2 months to 5 years of age (n = 249) were recruited from outpatient clinics in Gaborone and Francistown, and 29 were sampled from the pediatric wards at Princess Marina (Gaborone) and Nyangabgwe (Francistown) Hospitals. Nasopharyngeal specimens were collected and the carriage and antibiotic resistance of S. pneumoniae and H. influenzae type b were determined. Analyses of risk factors associated with carriage and resistance were performed.nnnRESULTSnStreptococcus pneumoniae was isolated from 69% of the outpatient children in Gaborone and 85% of the children in Francistown; the carriage rate in hospitalized children was 36% and 33% in Gaborone and Francistown, respectively. Approximately half of the isolates at both sites were resistant to at least one antibiotic, the most common being cotrimoxazole and penicillin. Resistance to three or more antibiotics (multiple resistance) was found in less than 10% of the isolates. Most penicillin resistance at both sites was at the intermediate level; however, almost 20% of the isolates demonstrated high-level resistance to cotrimoxazole. The most prevalent serogroups or serotypes of antibiotic-resistant isolates were 14, 19F, 19A, 6A, 6B, and 4. No risk factors for antibiotic resistance were identified. Haemophilus influenzae type b was isolated from 8% of the children in Gaborone and from 3% of the children in Francistown. Almost a third of the isolates were resistant to ampicillin.nnnCONCLUSIONSnThe high levels of antibiotic resistance in pneumococci isolated from children in Botswana suggest that the clinical management of meningitis and otitis media with a b-lactam antibiotic may fail in a significant proportion of cases and that empiric first-line use of cefotaxime or ceftriaxone for meningitis and higher dose amoxicillin (90 mg/kg/day) for otitis media is recommended. The levels of penicillin resistance in this study would not impact on the management of pneumonia with amoxicillin.

Impact of human immunodeficiency virus type 1 infection on the epidemiology and outcome of bacterial Meningitis in South African children

OBJECTIVEnTo define the impact that the human immunodeficiency virus type 1 (HIV-1) epidemic has had on the burden and outcome of bacterial meningitis in an area with a high prevalence of pediatric HIV-1 infection.nnnMETHODSnChildren less than 12 years of age with proven or suspected bacterial meningitis were enrolled in this study between March 1997 and February 1999, and their hospital records were retrospectively reviewed for clinical data.nnnRESULTSnSixty-two (42.2%) of the 147 children tested for HIV-1 infection were infected. Streptococcus pneumoniae (Pnc) exceeded Haemophilus influenzae type b (Hib) as the most important cause of meningitis in HIV-1-infected (74.2% vs. 12.9%, respectively) compared with uninfected children (29.4% vs. 42.3%, respectively, P less than 10(-5)). The estimated relative risk of Pnc meningitis was greater in HIV-1-infected than in uninfected children under 2 years of age (relative risk [RR] = 40.4; 95% confidence intervals [CI] = 17.7-92.2). Overall, HIV-1-infected children had a higher rate of mortality than uninfected children (30.6% vs. 11.8%, respectively, P = 0.01), and in particular, HIV-1-infected children with Pnc meningitis (60.8% vs. 36.0%, respectively, P = 0.04) had a poorer outcome.nnnCONCLUSIONSnStreptococcus pneumoniae has exceeded Hib as the most important pathogen causing bacterial meningitis in HIV-1-infected compared with uninfected children. Effective vaccination against Hib and Pnc should be evaluated to reduce the overall burden of bacterial meningitis in HIV-1-infected children.

Penicillin- and cephalosporin-resistant Streptococcus pneumoniae. Emerging treatment for an emerging problem.

The global emergence of pneumococci resistant to antimicrobial therapy has led to dilemmas in the management of pneumococcal infections. The principles of pharmacodynamics predict that penicillin and cephalosporin therapy of pneumonia will be successful against pneumococci with minimum inhibitory concentrations of penicillin up to 4 μg/ml. These predictions are supported by the observations of a number of recent clinical studies. Otitis media therapy is influenced by penicillin-resistance and current recommendations are that amoxicillin is the drug of choice for this infection, given at a double dose of 80 to 90 mg/kg/day. For the therapy of meningitis, cefotaxime or ceftriaxone in maximal doses is recommended and vancomycin may be added if cephalosporin-resistant strains are encountered with reasonable frequency in the population. The new fluoroquinolones with excellent antipneumococcal activity may be considered for use in the setting of pneumonia caused by highly resistant pneumococci and are under evaluation for the management of meningitis.

Epidemiology, Control and Treatment of Multiresistant Pneumococci

The epidemiology of pneumococcal resistance has changed during the past 5 years. At the beginning of the 1990s, resistant pneumococci were commonly isolated only in South Africa, Spain, Papua New Guinea and Eastern Europe (fig. 1). Within 5 years the spread of resistant strains has been dramatic, with particular increases documented in France and North America. In addition, countries for which no previous data were available are now documenting high rates of resistance. Antibiotic-resistant pneumococci represent> 20% of pneumococci documented in Japan[6] and> 60% of those reported in KoreaP] There are also major problems with resistant pneumococci in South America. Pneumococcal resistance is now distributed globally, with only a very few countries, mainly in Northern Europe, reporting resistance as a rare phenomenon. Nonetheless, in Iceland, during the period 1990 to 1995, there was a dramatic increase in pneumococcal resistance, which was associated with a single clone of multiresistant pneumococci of serotype 6B thought to have originated in Spain.[8] 1.2 Risk Factors

Persistence of antibodies to the Salmonella typhi Vi capsular polysaccharide vaccine in South African school children ten years after immunization

Between 10 and 11 years after children were vaccinated with Vi capsular polysaccharide of Salmonella typhi or meningococcal A + C control vaccine in a double blind randomized trial, we traced 83 subjects, aged 16-20 years. A blood sample was taken for determination of Vi antibody titres in both groups by radioimmunoassay. TO and TH titres were also done to assess if the participants had had recent exposure to typhoid fever. Fifty-eight percent of subjects in both groups had protective levels of Vi antibody against Salmonella typhi (a titre greater than 1 microgram ml-1). There was no significant difference in the levels of Vi antibodies in the cases versus the controls (p = 0.5). Two of the children who had received meningococcal A + C vaccine had recently had typhoid fever. Our data show that adolescents in typhoid endemic areas have high levels of Vi antibodies regardless of previous vaccination status, suggesting that Vi antibodies are acquired in adolescence by a large percentage of the population in this area. Moreover, Vi vaccination has led to ongoing antibody production in greater than 50% of Vi vaccinated children in an endemic area for a period of 10 years. Ongoing antigenic exposure may have contributed to these antibody levels.

Global practices of meningococcal vaccine use and impact on invasive disease

Abstract A number of countries now include meningococcal vaccines in their routine immunization programs. This review focuses on different approaches to including meningococcal vaccines in country programs across the world and their effect on the burden of invasive meningococcal disease (IMD) as reflected by pre and post-vaccine incidence rates in the last 20 years. Mass campaigns using conjugated meningococcal vaccines have lead to control of serogroup C meningococcal disease in the UK, Canada, Australia, Spain, Belgium, Ireland, and Iceland. Serogroup B disease, predominant in New Zealand, has been dramatically decreased, partly due to the introduction of an outer membrane vesicle (OMV) vaccine. Polysaccharide vaccines were used in high risk people in Saudi Arabia and Syria and in routine immunization in China and Egypt. The highest incidence region of the meningitis belt initiated vaccination with the serogroup A conjugate vaccine in 2010 and catch-up vaccination is ongoing. Overall results of this vaccine introduction are encouraging especially in countries with a moderate to high level of endemic disease. Continued surveillance is required to monitor effectiveness in countries that recently implemented these programs.

Pneumococcal resistance to the third-generation cephalosporins: clinical, laboratory and molecular aspects

Widespread use of third-generation cephalosporins appears to have selected cephalosporin-resistant pneumococci associated with the failure of these agents in the management of meningitis. Breakpoints of 0.5 mg/l for intermediate and 2 mg/l for full resistance are proposed for the treatment of pneumococcal meningitis. As no disc tests reliably identify these breakpoints, MIC or E test confirmation of third-generation cephalosporin resistance is recommended for all strains found resistant to a 1 mug oxacillin disk. Resistant strains can be selected in a single transformation event, with PBP 2X gene rearrangements conferring low level resistance and PBP 1A gene rearrangements conferring full resistance.

Antibiotic non-susceptibility among Streptococcus pneumoniae and Haemophilus influenzae isolates identified in African cohorts: a meta-analysis of three decades of published studies.

Management of community-acquired pneumonia caused by Streptococcus pneumoniae and Haemophilus influenzae type B (Hib) can be complicated by emerging antimicrobial non-susceptibility. We conducted a meta-analysis to examine the antibiotic susceptibility of community-acquired invasive infections with S. pneumoniae and Hib in Africa from 1978 to 2011. With the notable exceptions of widespread trimethoprim/sulfamethoxazole (SXT) and tetracycline non-susceptibility, the majority of pneumococci remain susceptible to ampicillin/amoxicillin. However, 23.8% of pneumococcal meningitis isolates are non-susceptible to penicillin. Similarly, Hib isolates show non-susceptibility to SXT, tetracycline, erythromycin and chloramphenicol. β-Lactamase production among Hib isolates is increasing, a new observation for Africa, but is mitigated somewhat by Hib vaccination scale-up. In summary, pneumococcal susceptibility to amoxicillin remains high throughout Africa, and amoxicillin can be effectively and safely used as first-line treatment for childhood pneumonia. Data support first-line treatment of bacterial meningitis with ceftriaxone or cefotaxime.

Septic arthritis due to Cryptococcus neoformans

Cryptococcal arthritis is rare. We report two cases, one of infection of the hip joint in a 56-year-old woman, the other of arthritis of the elbows and knees in a 4-year-old boy. Both patients were treated successfully with a combination of surgical drainage and antifungal therapy. The 15 previously published cases are reviewed. Immunodeficiency is noted in most reported cases commonly associated with the use of corticosteroids. The joint most often involved is the knee. Amphotericin B and 5-fluorocytosine have been used with success for treating this conditions. Ketoconoazole may have a role in the therapy of cryptococcal arthritis although information on the use of this agent is sparse.