José Luis Di Fabio

Evolution of Streptococcus pneumoniae serotypes and penicillin susceptibility in Latin America, Sireva-Vigía Group, 1993 to 1999

BACKGROUND Since 1993 the Pan American Health Organization has coordinated a surveillance network with the National Reference Laboratories of Argentina, Brazil, Chile, Colombia, Mexico and Uruguay aimed at monitoring capsular types and antimicrobial susceptibility of Streptococcus pneumoniae causing invasive disease in children <6 years of age. METHODS The surveillance system included children 6 years of age and younger with invasive disease caused by S. pneumoniae. The identification, capsular typing and susceptibility to penicillin of the isolates were conducted using a common protocol, based on standard methodologies. RESULTS By June, 1999, 4,105 invasive pneumococcal isolates had been collected mainly from pneumonia (44.1%) and meningitis (41.1%) cases. Thirteen capsular types accounting for 86.1% of the isolates (14, 6A/6B, 5, 1, 23F, 19F, 18C, 19A, 9V, 7F, 3, 9N and 4) remained the most common types during the surveillance period. Diminished susceptibility to penicillin was detected in 28.6% of the isolates, 17.3% with intermediate and 11.3% with high level resistance. Resistance varied among countries and increased during this period in Argentina, Colombia and Uruguay. Serotypes 14 and 23F accounted for 66.6% of the resistance. CONCLUSION These surveillance data clearly demonstrate the potential impact of the introduction of a conjugate vaccine on pneumococcal disease and the need for more judicious use of antibiotics to slow or reverse the development of antimicrobial resistance.Background. Since 1993 the Pan American Health Organization has coordinated a surveillance network with the National Reference Laboratories of Argentina, Brazil, Chile, Colombia, Mexico and Uruguay aimed at monitoring capsular types and antimicrobial susceptibility of Streptococcus pneumoniae causing invasive disease in children <6 years of age. Methods. The surveillance system included children 6 years of age and younger with invasive disease caused by S. pneumoniae. The identification, capsular typing and susceptibility to penicillin of the isolates were conducted using a common protocol, based on standard methodologies. Results. By June, 1999, 4105 invasive pneumococcal isolates had been collected mainly from pneumonia (44.1%) and meningitis (41.1%) cases. Thirteen capsular types accounting for 86.1% of the isolates (14, 6A/6B, 5, 1, 23F, 19F, 18C, 19A, 9V, 7F, 3, 9N and 4) remained the most common types during the surveillance period. Diminished susceptibility to penicillin was detected in 28.6% of the isolates, 17.3% with intermediate and 11.3% with high level resistance. Resistance varied among countries and increased during this period in Argentina, Colombia and Uruguay. Serotypes 14 and 23F accounted for 66.6% of the resistance. Conclusion. These surveillance data clearly demonstrate the potential impact of the introduction of a conjugate vaccine on pneumococcal disease and the need for more judicious use of antibiotics to slow or reverse the development of antimicrobial resistance.

Invasive Streptococcus pneumoniae Infection in Latin American Children: Results of the Pan American Health Organization Surveillance Study

Protein-polysaccharide conjugate vaccines against Streptococcus pneumoniae promise to be an effective public health intervention for children, especially in an era of increasing antimicrobial resistance. To characterize the distribution of capsular types in Latin America, surveillance for invasive pneumococcal infection in children < or = 5 years of age was done in six countries between February 1993 and April 1996. Fifty percent of 1,649 sterile-site isolates were from children with pneumonia, and 52% were isolated from blood. The 15 most common of the capsular types prevalent throughout the region accounted for 87.7% of all isolates. Overall, 24.9% of isolates had diminished susceptibility to penicillin: 16.7% had intermediate resistance and 8.3% had high-level resistance. Three customized vaccine formulas containing 7, 12, and 15 capsular types were found to have regional coverages of 72%, 85%, and 88%, respectively. This study emphasizes the need for local surveillance for invasive pneumococcal disease prior to the development and evaluation of protein-polysaccharide conjugate vaccines for children.

Laboratory-based surveillance of Streptococcus pneumoniae invasive disease in children in 10 Latin American countries: a SIREVA II project, 2000-2005.

Background: For the last 14 years the Pan American Health Organization has been promoting surveillance of invasive pneumococcal disease in Latin American children for better understanding of the disease tendencies regarding capsular types circulation in each country and susceptibility to antimicrobials. Methods: Laboratory-based surveillance data from 10 Latin American countries collected from 2000 to 2005 were analyzed, including serotype distribution and susceptibility to beta-lactam antibiotics. Results: Although 61 different capsular types were identified during the 6-year surveillance, 13 serotypes accounted for 86% of all isolates. These were consistently the most prevalent throughout the study period with serotype 14 predominating. Diminished susceptibility to penicillin was detected in 38% of all Streptococcus pneumoniae isolates, with the highest prevalence in Dominican Republic and Mexico. Decreased susceptibility to penicillin increased in Brazil and Colombia whereas decreased high resistance rates was recorded in Chile. Conclusions: These data indicate that 10 countries of the Region continue to have high quality laboratory-based surveillance for pneumococcal disease thus generating valuable information so that healthcare decision makers may prioritize interventions. The heptavalent vaccine will potentially cover from 52.4% to 76.5% of strains causing invasive pneumococcal disease and the 13 valent from 76.7% to 88.3%.

Population-based surveillance of pediatric pneumonia: use of spatial analysis in an urban area of Central Brazil

This study examined the spatial distribution of childhood community-acquired pneumonia detected through prospective surveillance in Goiânia, Brazil. Three spatial analysis techniques were applied to detect intra-urban geographic aggregation of pneumonia cases: Kernel method, nearest neighbor hierarchical technique, and spatial scan statistic. A total of 724 pneumonia cases confirmed by chest radiography were identified from May 2000 to August 2001. All cases were geocoded on a digital map. The annual pneumonia risk rate was estimated at 566 cases/100,000 children. Analysis using traditional descriptive epidemiology showed a mosaic distribution of pneumonia rates, while GIS methodologies showed a non-random pattern with hot spots of pneumonia. Cluster analysis by spatial scan statistic identified two high-risk areas for pneumonia occurrence, including one most likely cluster (RR = 2.1; p < 0.01) and one secondary cluster (RR = 1.3; p = 0.01). The data used for the study are in line with recent WHO-led efforts to improve and standardize pediatric pneumonia surveillance in developing countries and show how GIS and spatial analysis can be applied to discriminate target areas of pneumonia for public heath intervention.

Caracterización de aislamientos invasivos de S. pneumoniae, H. influenzae y N. meningitidis en América Latina y el Caribe: SIREVA II, 2000-2005

OBJECTIVES To analyze the phenotypical characteristics and the susceptibility to antibiotics of the circulating strains of Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis circulating in Latin America and the Caribbean from 2000-2005. Potential coverage by conjugate vaccines was evaluated. METHODS Conventional methods were used to study the distribution of the serotypes or serogroups of 17 303 strains of S. pneumoniae, 2 782 strains of H. influenzae, and 6 955 strains of N. meningitidis isolated from cases of pneumonia, meningitis, sepsis, bacteriemias, and other invasive processes. The antimicrobial susceptibilities of the study strains were evaluated. The isolates came from 453 sentinel surveillance sites in 19 countries in Latin America and four in the Caribbean, as part of the SIREVA II (Network Surveillance System for the Bacterial Agents Responsible for Pneumonia and Meningitis) project. RESULTS S. pneumoniae serotype 14 was the most frequently isolated (21.1%), especially in children under 6 years of age (29.1%). The potential coverages by hepta-, nona-, deca-, and trideca-valent antipneumonia conjugate vaccines were 59.0%, 73.4%, 76.5%, and 85.9%, respectively. Of the isolates, 63.3% were sensitive to penicillin. H. influenzae serotype b was present in 72.2% of the isolations from children under 2 years of age, whereas 8.6% produced serotypes a, c, d, e, and f, and 19.2% could not be serotyped. The rate of H. influenzae beta-lactamase-producing strains isolated from children under 2 years of age was 16.3%. The most frequent N. meningitidis serogroups were B (69.0%) and C (25.7%); 65.8% and 99.2% of the strains were susceptible to penicillin and rifampicin, respectively. CONCLUSIONS These results highlight the importance of comprehensive epidemiological surveillance of S. pneumoniae, H. influenzae and N. meningitidis in Latin America and the Caribbean. The great heterogeneity found in the distribution of S. pneumoniae serotypes among the countries studied could reduce immunization coverage. Conducting a specific analysis of each country to adjust the introduction of new conjugate vaccines and determine the best immunization plan is recommended.

Introducción de la vacuna conjugada contra Hib en Chile y Uruguay

In some countries, the invasive disease caused by Haemophilus influenzae type b (Hib) has been practically eliminated thanks to vaccination. However, in much of the developing world, meningitides and pneumonias caused by these bacteria continue to be a major cause of childhood morbidity and mortality, as well as high hospitalization costs. Because safe and effective conjugate vaccines are now available, the Special Program for Vaccines and Immunization of the Pan American Health Organization has recommended introducing them into the regular vaccination regimen of as many countries as possible. This has been done in Chile and Uruguay, where the Hib vaccine now forms part of the regular vaccination routine. When the vaccine was being introduced, both countries had difficulties they could have avoided if they had known of the experiences of other nations. Therefore, these two countries now offer the lessons they learned to other nations considering introducing the vaccine into their immunization programs. The most important lessons were to: strengthen the epidemiological surveillance system sufficiently in advance of introducing the vaccine; with the support of scientific societies, present the technical information that justifies introducing the vaccine; seek community backing and acceptance; precisely establish in advance the presentation and dosage of the vaccine that is most appropriate for the country; and be certain to have the political and legal decisions needed to ensure the continuity of Hib vaccination in the future.In some countries, the invasive disease caused by Haemophilus influenzae type b (Hib) has been practically eliminated thanks to vaccination. However, in much of the developing world, meningitides and pneumonias caused by these bacteria continue to be a major cause of childhood morbidity and mortality, as well as high hospitalization costs. Because safe and effective conjugate vaccines are now available, the Special Program for Vaccines and Immunization of the Pan American Health Organization has recommended introducing them into the regular vaccination regimen of as many countries as possible. This has been done in Chile and Uruguay, where the Hib vaccine now forms part of the regular vaccination routine. When the vaccine was being introduced, both countries had difficulties they could have avoided if they had known of the experiences of other nations. Therefore, these two countries now offer the lessons they learned to other nations considering introducing the vaccine into their immunization programs. The most important lessons were to: strengthen the epidemiological surveillance system sufficiently in advance of introducing the vaccine; with th support of sicentific societies, present the technical information that justifies introducing the vaccine; seek community backing and acceptance; precisely establish in advance the presentation and dosage of the vaccine that is most appropriate for the country; and be certain to have the political and legal decisions needed to ensure the continuity of Hib vaccination in the future.

Impacto de Streptococcus pneumoniae en las neumonías del niño latinoamericano

La neumonia adquirida en la comunidad es una de las principales causas de morbilidad y mortalidad en la infancia. Estudios realizados en paises en desarrollo indican que los cuadros de neumonia mas graves se asocian a causas bacterianas, con predominio de Streptococcus pneumoniae, seguido por Haemophilus influenzae tipo b. El manejo de esas infecciones en los menores de 2 anos se ve dificultado por la carencia de vacunas apropiadas y por la disminucion de la susceptibilidad de S. pneumoniae a la penicilina y a otros antibioticos. En 1993, por iniciativa del Sistema Regional de Vacunas (SIREVA) de la Organizacion Panamericana de la Salud y con la financiacion de la Agencia Canadiense para el Desarrollo Internacional (Canadian International Development Agency: CIDA), se diseno un estudio para identificar los tipos capsulares de S. pneumoniae que causan enfermedad invasora en los ninos latinoamericanos menores de 5 anos, con el proposito de determinar tanto la composicion ideal de una vacuna conjugada que pudiera emplearse en la Region como la susceptibilidad a la penicilina de los aislados de S. pneumoniae. La iniciativa fue aceptada por Argentina, Brasil, Colombia, Chile, Mexico y Uruguay. En este informe se analiza la informacion sobre la neumonia por S. pneumoniae generada en los paises participantes. Se captaron 3 393 ninos con infecciones sistemicas por S. pneumoniae, de las cuales 1 578 correspondian a neumonias. El analisis se concentro en los 1 409 casos de neumonia de Argentina, Brasil, Colombia, Mexico y Uruguay. La distribucion por edades evidencio un franco predominio de los menores de 2 anos (63,8%). Se identificaron 12 tipos capsulares prevalentes, de los cuales los serotipos 14, 5 y 1 ocuparon los tres primeros lugares en la mayoria de los paises. En el periodo 1993-1998, la resistencia a la penicilina aumento en los cinco paises; al comienzo del estudio, los mayores porcentajes correspondieron a Mexico (47,0%) y los menores a Colombia (12,1%). La resistencia a la penicilina se asocio con un reducido numero de serotipos capsulares, fundamentalmente el 14 y el 23F, el primero resistente a la penicilina y a la trimetoprima-sulfametoxazol, y el segundo multirresistente. La frecuencia de la resistencia a la trimetoprima-sulfametoxazol fue elevada en todos los paises y el valor maximo correspondio a Argentina (58,0%). La disminucion de la susceptibilidad al cloranfenicol tuvo baja frecuencia, salvo en Colombia (23,4%). La resistencia a la eritromicina fue baja en todos los paises y todos los aislados fueron sensibles a la vancomicina.Community-acquired pneumonia is one of the leading causes of infant morbidity and mortality. Studies conducted in developing countries indicate that the most serious symptoms of pneumonia are associated with bacterial causes, mainly Streptococcus pneumoniae, followed by Haemophilus influenzae type b. Managing those infections in children under two years of age is hindered by the lack of appropriate vaccines and by the decreased susceptibility of S. pneumoniae to penicillin and other antibiotics. In 1993, at the initiative of the Regional System for Vaccines of the Pan American Health Organization, and with funding from the Canadian International Development Agency, a study was designed to identify the S. pneumoniae capsular types that cause invasive disease in Latin American children under 5 years of age. The objective of the study was to determine the ideal composition of a conjugate vaccine that could be used in Latin America, and the penicillin susceptibility of the S. pneumoniae isolates. The initiative was undertaken in Argentina, Brazil, Chile, Colombia, Mexico, and Uruguay. This report analyzes the information that the participating countries generated on pneumococcal pneumonia. A total of 3,393 children were found with systemic S. pneumoniae infections, of which 1,578 corresponded to pneumonias. The analysis focused on 1,409 cases of pneumonia in Argentina, Brazil, Colombia, Mexico, and Uruguay. Of the children, 63.8% of them were under two years of age. Twelve prevalent capsular types were identified, of which serotypes 14, 5, and 1 were the three most common in the majority of the countries. At the beginning of the study the highest level of penicillin resistance was found in Mexico (47.0%), and the lowest in Colombia (12.1%). Over the 1993-1998 period, resistance to penicillin increased in the five countries. Penicillin resistance was associated with a small number of capsular serotypes, mainly 14 and 23F. The first of those serotypes was resistant to penicillin and to trimethoprim-sulfamethoxazole, and the second was multiresistant. The frequency of resistance to trimethoprim-sulfamethoxazole was high in all of the countries; Argentina had the highest level, 58.0%. A decrease in susceptibility to chloramphenicol was uncommon, except in Colombia, where there was a resistance level of 23.4%. Resistance to erythromycin was low in all the countries, and all the isolates were susceptible to vancomycin.

Considerations for Combination Vaccine Development and Use in the Developing World

As more vaccines are developed and become available, combination vaccines will provide a way of delivering multiple antigens to avoid multiple injections and complications in the regular immunization schedules. The advantages of combination vaccines are that they decrease the discomfort of vaccine recipients and parents and also reduce the delivery cost of vaccines. We address some of the issues related to the use of combination vaccines in the developing world. Which vaccines are needed? Do developing countries have the appropriate infrastructure to deliver them? Can vaccines become affordable for countries with low incomes? And what is really needed to achieve the goal of providing developing countries with new vaccines of epidemiologic significance in a timely fashion?

Presence of international multiresistant clones of Streptococcus pneumoniae in Colombia.

In Colombia, penicillin resistance of Streptococcus pneumoniae invasive isolates recovered from children less than 5 years old has increased from 10% in 1994 to 49.4% in 1999, suggesting the circulation of international resistant clones in the country. A total of 167 S. pneumoniae invasive isolates with diminished susceptibility to penicillin (DSP) were studied. The techniques used were pulsed-field gel electrophoresis (PFGE) and restriction fragment length polymorphism (RFLP) of penicillin-binding proteins (PBPs) genes (2B, 2X, and 1A). Forty-nine serotype 23F isolates were grouped in two clusters: 15 (31%) multiresistant isolates showed PFGE pattern A and PBP I profile, thus making them indistinguishable from Spain23F-1 clone, and 34 (69%) with PFGE pattern C, PBP II profile, and intermediate level resistance (ILR) to penicillin and TMP-SMX, features unique to a Colombian clone. Fifty-five serotype 14 isolates were assigned to PFGE B pattern, PBP III profile, having high-level resistance to penicillin, and TMP-SMX, similar to the France9V variant 14. This same pattern was present in five capsular type 9V isolates. Four serotype 14 isolates were assigned to PFGE pattern F, and appeared to be similar to Slovakia(14)-10 PFGE pattern, although they had different PBP profiles. Nine capsular type 6B and one 6A isolates belonged to PFGE pattern M, similar to Spain6B-2, although they showed different PBP profiles. The remaining 44 isolates, corresponding to serotypes 14, 6B, 19F, and 34, showed variable PFGE and PBP patterns. These results show that as many as two international clones may be circulating in Colombia as well as a unique, widely distributed 23F clone with ILR to penicillin. Additionally, some Colombian isolates capsular type 14 and 6B might be related to Slovakia(14)-10 Spain6B-2 clones, respectively.

Cepas invasivas de pneumococo isoladas de crianças e adolescentes em Salvador

OBJETIVOS: descrever resistencia antimicrobiana e sorotipos de cepas de pneumococo. METODOS: durante 57 meses, foi conduzida uma vigilância de cepas invasivas de pneumococo de pacientes com idade <20 anos. O pneumococo foi identificado pelos testes de solubilidade da bile e optoquina. A resistencia a penicilina foi avaliada com o disco de oxacilina (1µg) e, para as cepas nao suscetiveis, foi determinada a concentracao inibitoria minima. Provas de difusao de disco e de microdiluicao em placa foram utilizadas para avaliacao da resistencia a outros antimicrobianos. Reacao de Neufeld-Quellung foi realizada para sorotipagem. RESULTADOS: dos 70 pacientes, 57,1% eram do sexo masculino. A mediana da idade foi 1,92 anos (media 3,19 ± 3,66 anos, variando de um mes a 19,5 anos), tendo 52,9% e 81,4% dos pacientes idade <2 anos e <5 anos, respectivamente. As cepas foram isoladas do sangue (91,4%), liquor (2,9%), liquidos pleural (2,9%), peritonial (1,4%) ou de abscesso (1,4%), de pacientes com pneumonia (77,1%), febre sem sinais localizatorios (10,0%), meningite (4,3%) e outros diagnosticos (8,6%). Resistencia foi detectada a penicilina (20,0%), ao sulfametoxazol-trimetoprim (65,7%), a tetraciclina (21,4%), a ofloxacina (6,3%), a eritromicina (5,7%) e a clindamicina (2,9%). Nao houve resistencia ao cloranfenicol ou a vancomicina. Entre as cepas nao suscetiveis a penicilina, resistencia absoluta foi detectada em uma, a mesma que apresentou resistencia intermediaria a cefotaxima. Os sorotipos mais frequentes foram: 14 (22,9%), 5 e 6A (10,0% cada), 6B e 19F (8,6% cada), 9V, 18C e 23F (5,7% cada). Das cepas resistentes a penicilina, 71,4% pertenciam ao sorotipo 14, 14,3% aos sorotipos 6B e 19F (cada). CONCLUSOES: das 70 cepas, 67,2% tem sorotipos incluidos na vacina pneumococica heptavalente conjugada, assim como estao incluidos todos os sorotipos que apresentaram resistencia a penicilina.