María Catalina Pírez

Impact of Universal Pneumococcal Vaccination on Hospitalizations for Pneumonia and Meningitis in Children in Montevideo, Uruguay

Background: In March 2008, Uruguay included PCV7 into the routine vaccination program, in a 2 + 1 schedule for children <2 years of age. Catch-up immunization was offered to children born in 2007. Greater than 95% of children received their first and second doses. The aim of this study was to assess the effect of this strategy. Methods: Annual hospitalization rates (per 10,000 discharges) for community-acquired pneumonia (CAP) in children <14 years of age and pneumococcal meningitis are described prior to PCV7 vaccination (2005–2007), during the year of implementation (2008) and following vaccine introduction (2009). Data regarding age, diagnosis, vaccination status, and pneumococcal serotype were obtained from Hospital Pereira Rossell databases and vaccination records. Results: Comparison of hospitalization rates for CAP and pneumococcal-CAP (P-CAP) between prevaccine years (2005–2007) and the year after vaccination (2009) decreased significantly in all children by 56% and 48.2%, respectively. Significant reduction was observed for vaccine serotype P-CAP (serotype 14 P-CAP decreased from 26.6 to 2.5 per 10,000 discharges) in children <2 years of age. A significant reduction in pneumococcal meningitis of 59% was seen in this age group; median rates prevaccination decreased from 17 (12.2–24.9) to 7 (3–11.8) after the administration of vaccine. No vaccine failures for P-CAP or pneumococcal meningitis were seen in fully immunized children. Conclusions: One year after PCV7 introduction into the routine vaccination schedule of Uruguay, there was a rapid and significant reduction in rates of CAP, P-CAP, and pneumococcal meningitis in children <2 years of age.

Intracellular Bacteria in the Pathogenesis of Escherichia coli Urinary Tract Infection in Children

BACKGROUND Uropathogenic Escherichia coli (UPEC) is the most common agent of urinary tract infection (UTI). The classic model of pathogenesis proposes the ascent of UPEC by the urethra and external adherence to the urothelium. Recently, the ability of UPEC to invade urothelial cells and to form intracellular bacterial communities (IBCs) has been described. METHODS The objective of the present study was to determine the presence of intracellular bacteria (IB) in children with UTI caused by E. coli and to characterize its virulence attributes and its relation with clinical outcomes. One hundred thirty-three children with E. coli UTI who attended a reference childrens hospital between June and November 2012 were included. Urine samples were analyzed by optical and confocal microscopy looking for exfoliated urothelial cells with IB. Phylogenetic group and 24 virulence factors of UPEC were determined using multiplex polymerase chain reaction. Medical records were analyzed. RESULTS The presence of IB was detected in 49 of 133 (36.8%) samples by confocal microscopy, in 30 cases as IBC, and in 19 as isolated intracellular bacteria (IIB). Only 50% of these cases could be detected by light microscopy. Seventy-four medical records were analyzed, 34 with IBC/IIB, 40 without IB. Any virulence gene was associated with IBC/IIB. The presence of IBC/IIB was associated with recurrent UTI (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.3-9; P = .017), especially in children without urinary tract functional or morphological abnormalities (OR, 8.0; 95% CI, 2.3-27.4; P = .000). IBCs were associated with lower urinary tract syndrome (OR, 3.6; 95% CI, 1.1-11.8; P = .05) and absence of fever (P = .009). CONCLUSIONS IBCs/IIB could explain a high proportion of children with recurrent UTI.

Changes in hospitalizations for pneumonia after universal vaccination with pneumococcal conjugate vaccines 7/13 valent and haemophilus influenzae type b conjugate vaccine in a Pediatric Referral Hospital in Uruguay.

Background: In 1994, Uruguay included Haemophilus influenzae b (Hib) conjugated vaccine in a 3 + 1 schedule. In March 2008, 7-valent pneumococcal conjugate vaccines (PCV7) was included in a 2 +1 schedule. In 2010, 13-valent PCV replaced PCV7. Catch-up immunization was offered. The aim of this study was to describe the etiology of community-acquired pneumonia (CAP) in children 0–14 years of age hospitalized at the Hospital Pediatrico-Centro Hospitalario Pereira Rossell between 2003 and 2012. Methods: Annual hospitalization rates (per 10,000 discharges) for CAP and bacterial-confirmed CAP in children 0–14 years of age was described prior PCV7 vaccination (2003–2007), during the year of implementation of PCV7 (2008) and after the introduction of PCV7 (2009–2012). Data regarding age, strains isolated from pleural fluid and/or blood, vaccination status, pneumococcal and H. influenzae serotypes were obtained from Hospital Pediatrico-Centro Hospitalario Pereira Rossell databases and vaccination records. Results: Hospitalization rates for CAP and pneumococcal CAP between prevaccine years and the last year after introduction of vaccination with PCV (2012) significantly decreased by 78.1% and 92.4%, respectively. Significant reduction for 13-valent PCV vaccine serotypes and significant increase for nonvaccine serotypes was observed. A decrease in Staphylococcus aureus pneumonia was observed. Hospitalization rates for H. influenzae CAP remain stable before and after pneumococcal vaccination. Conclusions: Three years after PCV7/13 introduction into the routine vaccination schedule, there was a rapid and significant reduction in rates of CAP and P-CAP. An increase of etiology of CAP by other agents was not observed.

Standard case management of pneumonia in hospitalized children in Uruguay, 1997 to 1998

Objective. To report the results of the use of antimicrobial guidelines for the management of children with community-acquired bacterial pneumonia. Methods. Admittance and discharge criteria and algorithms for diagnosis and treatment were established. The decision to treat with antibiotics was based on radiologic findings in pneumonia with pulmonary consolidation and left to the attending physician’s criteria in the remaining cases. The use of antibiotics was limited to penicillin and derivatives (ampicillin, amoxicillin) and macrolides. Results. Of the 1163 children treated as bacterial pneumonia, hospitalized in public and private health facilities in Montevideo from September, 1997, through September, 1998, standard case management was applied in 1082 (93%). Age distribution was: <1 month, 1%; between 1 and 11 months, 29%; between 1 and 5 years, 50%; >5 years, 20%. Chest radiography showed evidence of pulmonary consolidation in 843 children (73%). Bacteria were detected in blood culture and/or pleural fluid of 57 children (5%). In 51 the identified microorganism was Streptococcus pneumoniae, susceptible to penicillin in 30, intermediate in 6 and resistant in 5 (maximum MIC, 4 &mgr;g/ml); in 10 cases etiologic diagnosis was made by antigen detection. Empyema was present in 62 children (5.3%); 38 (3.27%) required treatment in an intensive care unit; and 5 (0.4%) died. Conclusions. Compliance with standard case management was highly satisfactory. Outcome of children treated with penicillin and derivatives was good, including children with empyema and pneumatocele and two patients with penicillin-resistant S. pneumoniae. At the present time S. pneumoniae resistant to penicillin is not an important problem in children with pneumonia in Uruguay. Surveillance of identified microorganisms and their antimicrobial susceptibility must continue.

Ampicillin and penicillin concentration in serum and pleural fluid of hospitalized children with community-acquired pneumonia.

Background: Optimal therapeutic efficacy of β-lactam antibiotics for treatment of pneumococcal pneumonia is thought to be associated with the serum concentration greater than the minimum inhibitory concentration for 40–50% of the interdose interval at site of infection. Objective: Establish whether intravenous administration of ampicillin 400 mg/kg/day or penicillin 200,000 IU/kg/day in 6 divided doses reaches serum and or pleural concentrations above 4 μg/ml for at least 40% of the interdose interval. Materials and Methods: Hospitalized healthy children 1 month–14 years old with community-acquired bacterial pneumonia and empyema were eligible. Blood samples were obtained 30 min (C1) and 3 h (C2) after an antibiotic dose. Pleural fluid samples were obtained 1 and 4 h after the same dose in which blood samples were obtained. The concentrations were measured by high performance liquid chromatography. Results: The study included 17 patients treated with ampicillin and 13 treated with penicillin. For ampicillin, mean serum concentrations were C1 37.3 ± 19 μg/ml and C2 11 ± 10.2 μg/ml and mean pleural fluid concentrations were C1 25.8 ± 9.9 μg/ml and C2 16.2 ± 7.9 μg/ml. For penicillin, mean serum concentrations were C1 21.8 ± 16.4 μg/ml and C2 23.9 ± 3.4 μg/ml. Mean pleural fluid concentrations were C1 10.9 ± 2.2 μg/ml and C2 7.7 ± 3.4 μg/ml. In 8 of 30 patients, serum C2 was <4 μg/ml; in all of them serum concentrations were >4 μg/ml for >40% of the interdose interval. Conclusions: This study of the pharmacokinetics of β-lactam antibiotics in children with bacterial pneumonia may help in the development of therapeutic guidelines for the treatment of pneumococcal pneumonia.

Enteropathogens Associated with Acute Diarrhea in Children from Households with High Socioeconomic Level in Uruguay

Infectious diarrhea, a common disease of children, deserves permanent monitoring in all social groups. To know the etiology and clinical manifestations of acute diarrhea in children up to 5 years of age from high socioeconomic level households, we conducted a descriptive, microbiological, and clinical study. Stools from 59 children with acute community-acquired diarrhea were examined, and their parents were interviewed concerning symptoms and signs. Rotavirus, adenovirus, and norovirus were detected by commercially available qualitative immunochromatographic lateral flow rapid tests. Salmonella, Campylobacter, Yersinia, and Shigella were investigated by standard bacteriological methods and diarrheagenic E. coli by PCR assays. We identified a potential enteric pathogen in 30 children. The most frequent causes of diarrhea were enteropathogenic E. coli (EPEC), viruses, Campylobacter, Salmonella, and Shiga-toxin-producing E. coli (STEC). Only 2 patients showed mixed infections. Our data suggest that children with viral or Campylobacter diarrhea were taken to the hospital earlier than those infected with EPEC. One child infected with STEC O26 developed “complete” HUS. The microbiological results highlight the importance of zoonotic bacteria such as atypical EPEC, Campylobacter, STEC, and Salmonella as pathogens associated with acute diarrhea in these children. The findings also reinforce our previous communications about the regional importance of non-O157 STEC strains in severe infant food-borne diseases.

Seroprevalence of anti-polio antibodies in a population 7 months to 39 years of age in Uruguay: implications for future polio vaccination strategies.

This study evaluated the seroprevalence of poliovirus types 1, 2 and 3 antibodies and vaccination coverage in 780 subjects aged between 7 months and 39 years in Montevideo, Uruguay, where oral polio vaccine (OPV) is used. Antibody titers were measured and seroprotection rates and geometric mean titers (GMTs) were compared among four age groups. Vaccination histories were recorded from documents and interviews. Seroprotection rates ranged from 72% to 95% in children aged 7-23 months, 31-77% in 2-9-year olds, 14-45% in 10-19-year olds and 20-59.5% in 20-39-year olds. Seroprotection decreased significantly with increasing age (p<0.05). Polio vaccination coverage was >90% for the two youngest age groups. These results could help guide public policy decisions regarding polio vaccination, and support the use of inactivated polio vaccine following cessation of OPV.

Enfermedad neumoccócica invasora en recién nacidos, antes y después de la vacunación universal con vacuna conjugada 7 y 13 valente en Uruguay

INTRODUCTION Streptococcus pneumoniae infections are not frequent in neonates, but presents high morbidity and mortality. In 2008, the 7-valent pneumococcal conjugate vaccine (PCV) was introduced in the childhood vaccination schedule and then replaced by 13-valent PCV in 2010. First dose is given at 2 months of age. Protection of neonates is expected with universal vaccination. OBJECTIVE To describe the clinical presentation, microbiology and outcome of neonates with pneumococcal invasive infections (PII) detected in two hospitals in Uruguay in 2001-2007 (pre-vaccination), 2008 (intervention) and 2009-2013 (post-vaccination). METHODS A descriptive, retrospective study was done at Pereira Rossell Hospital and Paysandú Hospital. All isolates of S. pneumoniae obtained from normally sterile fluids were included. Data were obtained from the clinical records and the microbiology laboratory. A statistical analysis with absolute frequencies, relative, rates and relative risk was performed. RESULTS 25 neonates were enrolled with diagnosis of: sepsis (n = 13), meningitis (n = 9), bacteremia (n = 1), pneumonia with empyema (n = 1) and pneumonia (n = 1). The incidence of PII in the prevaccination period was 19/25, with a rate of 0.30/1,000 births, compared to post-vaccination rate of 0.04/1,000. The relative risk was 5.9. 6/20 (30%) cases of death were reported (meningitis n = 3; sepsis n = 2; empyema n = 1). Most common serotypes were 5 and 1 (14/25) and 24/25 strains were susceptible to penicillin. DISCUSSION The symptoms were indistinguishable to infections caused by other pathogens. PII cases decreased and no deaths occurred in the post-vaccination period. No increase in non-vaccine serotypes was observed.

Urinary tract infection in Uruguayan children: Aetiology, antimicrobial resistance and uropathogenic Escherichia coli virulotyping

Uropathogenic Escherichia coli (UPEC) is the most frequent cause of urinary tract infection (UTI). Virulence factors (VFs) of UPEC in children are not well known. Circulating antibiotic resistance mechanisms in the community are increasing. In this study, the aetiological agents of UTI and antibiotic resistance mechanisms of 124 strains isolated from urine cultures from children with community-acquired UTI were determined. Virulotyping of isolated E. coli strains was also described. β-Lactam, fluoroquinolone and sulfonamide resistance genes as well as integrons were detected by PCR. E. coli phylogenetic groups and 25 VFs were sought by multiplex PCR. E. coli was the most frequent aetiological agent (88.7%), of which 48.2% belonged to phylogenetic group D and 35.5% to group B2. Moreover, 81.8% were considered UPEC and >93% had virulence structures, with kpsMTII, fimH and iutA being the most frequent. Most of the E. coli isolates were susceptible to amoxicillin/clavulanic acid (AMC) (87.3%), nitrofurantoin (97.3%), cefuroxime and third-generation cephalosporins (100%). Resistance levels to oxyimino-cephalosporins were higher in non-E. coli isolates, with circulation of integrons, blaCTX-M-2 and blaCMY-2 detected in the community. Moreover, 8.1% of isolates were resistant to fluoroquinolones, with qnrB found in two isolates. Resistance to trimethoprim/sulfamethoxazole was found in 37.9% of isolates, with 85.5% harbouring sul genes. E. coli isolated from children with UTI presented high rates of VFs. Nitrofurantoin, AMC and cefuroxime would be suitable antibiotics to treat UTI in children. However, the presence of integrons (fundamentally class 1) and circulation of broad-spectrum β-lactamases in the community makes continuous surveillance necessary.

Epidemiological burden of invasive pneumococcal disease in children and adolescents with predisposing risk factors

OBJECTIVE Some medical conditions constitute important risk factors for the development of invasive pneumococcal diseases in children and adolescents aged from 5 to 19 years. Conjugate vaccines have potential efficacy in this scenario, but are not available in many Latin American public healthcare systems for this age group. This study aimed to estimate the preventable fraction of invasive pneumococcal diseases among individuals aged from 5 to 19 years with associated risk factors for its development. METHODS Data regarding the Latin America population, risk factors prevalence and conjugate vaccines efficacy were obtained from the literature. RESULTS Total population at risk ranged from 17.3 to 64.6 million of individuals and asthma was the most impacting risk factor. According to SIREVA, PCV13 provided a 62.9% serotypes coverage in individuals from 5 to 29 years in 2012, potentially increasing the covered population from [8,338,457-31,057,620] with PCV10 to [10,906,356-40,622,078] with PCV13. To date, according to available efficacy data, the hypothetically immunized population ranged from 11.4 to 42.4 million, representing 7.0% to 26.0% of the total population in this age group. CONCLUSIONS Vaccination in risk groups should be encouraged, as it potentially contributes to the reduction in the number of cases of invasive pneumococcal disease.