Epidemiological Aspects of Maternal and Congenital Toxoplasmosis in Panama.

In Panama, epidemiological data on congenital toxoplasmosis are limited, making it difficult to understand the scope of clinical manifestations in the population and factors that may increase the risk of infection. This study provides insight into the epidemiological situation of maternal and congenital toxoplasmosis in Panama and contributing information on the burden of this disease in Central America. Blood samples were collected from 2326 pregnant women and used for the detection of anti-T. gondii antibodies. A high seroprevalence (44.41%) was observed for T. gondii infection in pregnant women from different regions of Panama, with an estimated incidence rate of congenital toxoplasmosis of 3.8 cases per 1000 live births. The main risk factors associated with T. gondii infection using bivariate statistical analysis were an elementary level education and maternal age range of 34-45 years. Multivariate statistical analyses revealed that in some regions (San Miguelito, North and West regions), the number of positive cases correlated with the presence of pets, stray dogs and the consumption of poultry. In other regions (East and Metropolitan regions), the absence of pets was considered a protective factor associated with negative cases, while the presence of stray cats and the age range of 25-34 years did not represent any risk in these regions.

Tumor necrosis factor alpha/cachectin and interleukin 1 beta initiate meningeal inflammation.

Although previous studies using human cytokines in rabbits and rats have provided evidence of the participation of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) in the meningeal inflammatory cascade, the results obtained by several groups of investigators have been discordant or, at times, contradictory. In the present study, homologous cytokines were applied to the rabbit meningitis model. Intracisternal administration of 10(2)-10(5) IU of purified rabbit TNF-alpha (RaTNF-alpha) produced significant cerebrospinal fluid (CSF) inflammation. A similar response was observed after intracisternal inoculation of 5-200 ng of rabbit recombinant IL-1 beta (rrIL-1 beta). Preincubation of these two mediators with their specific antibodies resulted in an almost complete suppression of the CSF inflammatory response. In animals with Haemophilus influenzae type b lipooligosaccharide-induced meningitis, intracisternal administration of anti-rrIL-1 beta, anti-RaTNF-alpha, or both resulted in a significant modulation of meningeal inflammation. Simultaneous administration of 10(3) IU of RaTNF-alpha and 5 ng of rrIL-1 beta resulted in a synergistic inflammatory response manifested by a more rapid and significantly increased influx of white blood cells into the CSF compared with results after each cytokine given alone. These data provide evidence for a seminal role of TNF-alpha and IL-1 beta in the initial events of meningeal inflammation.

Pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection.

Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (approximately 12.5 mg/kg of body weight [BW] for children weighing < 40 kg and 500 mg for children weighing > or = 40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to < 6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW(0.696). An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose.

[Economic impact of rotavirus vaccination in Panama]. / Impacto económico de la vacuna antirrotavirus en Panamá

INTRODUCTION: Rotavirus (RV) gastroenteritis (GE) causes a significant health and economic burden in Panama. The main objective of this study is to estimate the healthcare costs and the cost-effectiveness of vaccination in Panama from the societal perspective. METHODS: An economic model was constructed, using published epidemiological data, country-specific cost estimates, and vaccine efficacy data. The main outcome measures were disease burden, economic burden and the incremental cost-effectiveness ratio (US$/DALY and US$/life saved) of vaccination. RESULTS: In Panama, among children during the first five years of life, it is estimated that due to RV GE, 283 per 1,000 have a clinic visit, 24 per 1,000 are hospitalized, and 0.53 per 1,000 die. For every 1,000 children born, RV infection results in US$16,463 in total costs during their first five years of life. An estimated US$862,388 may be spent annually on treatment of outpatient and hospitalized cases in Panama. Vaccination would prevent 65% of the associated deaths, 68% of hospitalizations, 69% of outpatient visits and 65% of associated DALY (Disability Adjusted Life Years). From the societal perspective, RV vaccination produces a cost-effectiveness ratio of US$487 per DALY when the price of the vaccine is US$7.50 per dose. CONCLUSIONS: Vaccination can effectively reduce the disease burden and healthcare costs of RV GE in Panama.

Enhanced attenuation of meningeal inflammation and brain edema by concomitant administration of anti-CD18 monoclonal antibodies and dexamethasone in experimental Haemophilus meningitis.

Antiinflammatory therapy has been shown to reduce the adverse pathophysiological consequences that occur in bacterial meningitis and to improve outcome from disease. In the present study, modulation of two principal steps of the meningeal inflammatory cascade was accomplished by concomitant administration of dexamethasone to diminish overproduction of cytokines in response to a bacterial stimulus and of a monoclonal antibody directed against adhesion-promoting receptors on leukocytes to inhibit recruitment of white blood cells into the subarachnoid space. Dexamethasone and antibody therapy produced a marked attenuation of all indices of meningeal inflammation and reduction of brain water accumulation after H. influenzae-induced meningitis in rabbits compared with results of each agent given alone and of untreated animals. In addition, the enhanced host's meningeal inflammatory reaction that follows antibiotic-induced bacterial lysis was profoundly ameliorated when dual therapy was administered without affecting clearance rates of bacteria from cerebrospinal fluid and vascular compartments. The combination of both therapeutic approaches may offer a promising mode of treatment to improve further the outcome from bacterial meningitis.

[Seroprevalence of cytomegalovirus infection in puerperal women and its impact on their newborns]. / Seroprevalencia de la infección por citomegalovirus en puérperas y su impacto neonatal.

INTRODUCTION: Cytomegalovirus (CMV) is the most frequent etiologic agent associated with perinatal infections. The incidence of this infection is higher in developing countries. The seroprevalence of CMV infection among pregnant women and its impact on newborns have not been studied in Panama and there are a few publications on this health problem in Latin America. OBJECTIVE: The purpose of this study was to determine the seroprevalence of CMV infection in puerperal women and CMV-related morbidity in the neonates of seropositive mothers. PATIENTS AND METHODS: A total of 316 blood samples from puerperal women and 317 urine samples from their newborns were obtained to determine CMV IgG and the polymerase chain reaction CMV test respectively. Risk factors such as parity, socioeconomic status and educational level were analyzed. RESULTS: The seroprevalence of CMV was 84 % and the incidence of congenital CMV infection in the newborns of seropositive women was 0.8 %. Two cases of congenital CMV infection were diagnosed, one of which showed clinical signs at birth, but neither of the newborns showed neurological or audiological sequels in the first 11 months of life. There were no correlations between positive serology and parity, socioeconomic status or educational level in the mothers studied. CONCLUSIONS: Although neither of the newborns diagnosed with congenital CMV infection showed clinical signs at the time of this report, we believe that the incidence of 0.8 % found in this study should be kept in mind with a view to evaluating the possibility of including CMV diagnostic tests in neonatal screening and introducing measures to prevent seronegative mothers from becoming infected.

[Dengue infection in children and adolescents in Panama]. / Dengue pediátrico en Panamá.

BACKGROUND: Dengue is a serious emerging infectious disease and constitutes a major international health concern. MATERIAL AND METHODS: All reports of confirmed dengue infection in patients aged less than 18 years old between 2000 and 2005 were included. A confirmed diagnosis was established by culture of the virus within the first 3 days of symptom onset or by serologic assays 5-30 days after symptom onset. Clinical and epidemiological features were analyzed. RESULTS: A total of 457 patients were included (57.6 % female). The median age was 13 years (IQR 5 6). A greater number of cases were detected in urban areas and during the rainy season (May-November). Two epidemics were reported in 2001 (33.9 %) and the first eight months of 2005 (23.1 %). The most prevalent symptoms were fever (95.2 %), severe headache (74.2 %), chills (65.9 %), rash (63.5 %), myalgias (51.9 %) and retro-orbital pain (51.6 %). No significant differences were found between male and female patients. Significant differences in clinical features were found when the patients were divided into 3 groups; < 5 years old, 6-10 years old and > 10 years old. Fifty-three percent of the patients had had previous contact with a dengue-infected individual. There were 7 patients with dengue hemorrhagic fever, 4 of whom died. CONCLUSIONS: Dengue virus infection is still a major health problem in Panama. To achieve effective control of dengue, further epidemiological studies, such as our own, are needed to design appropriate preventive measures.

Specific detection of Haemophilus influenzae type b lipooligosaccharide by a polymyxin B monoclonal antibody assay.

A monoclonal antibody (MAb)-based enzyme immunoassay was developed for detection of Haemophilus influenzae type b (Hib) lipooligosaccharides (LOS). The high affinity of polymyxin B for lipid A was used to bind the Hib LOS to microtiter wells. The immobilized LOS was detected with MAbs directed against the oligosaccharide component of Hib endotoxin. Hib LOS concentrations were measured in in vitro samples and in cerebrospinal fluid (CSF) sample obtained from rabbits with experimental Hib meningitis. The sensitivity of the assay was 1 ng LOS/ml sample and the results obtained with this assay correlated significantly with those obtained with the standard Limulus amebocyte lysate assay. This new assay provides a method for specific detection of Hib LOS in CSF samples and in aqueous laboratory fluids. This general methodology should also be useful for experimental research involving specific LPS/LOS molecules.

Cefepime in the empiric treatment of meningitis in children.

BACKGROUND: Because the introduction of extended spectrum cephalosporins into pediatric practice offers a number of choices for treatment, we review efficacy studies of cefepime monotherapy in the treatment of bacterial meningitis in children. METHODS: Two open, randomized, comparative studies assessed the efficacy of cefepime empiric monotherapy in the treatment of bacterial meningitis in 345 pediatric patients. These studies were conducted in Latin America and compared cefepime (50 mg/kg/dose every 8 h) with either cefotaxime (50 mg/kg/dose every 6 h) or ceftriaxone (50 mg/kg/dose every 12 h). Patients 2 months to 14 years old who had clinical signs and symptoms consistent with a central nervous system infection were enrolled. Efficacy was based on clinical and bacteriologic response. RESULTS: Integrated results from the Latin American studies indicated a 75% cure rate with cefepime vs. a 78% cure rate with comparator, among evaluable patients. Overall the rate of treatment failure was 12%. Haemophilus influenzae had the highest bacterial eradication rate (97% overall), and rates were comparable in cefepime and comparator arms. Eradication rates for Neisseria meningitidis were equally high in both treatment arms (95% overall), and the eradication rate for Streptococcus pneumoniae was 92% overall. Of the patients with S. pneumoniae isolated during pretreatment (from either cerebrospinal fluid or blood), 11 (16 isolates in total) had their isolates tested against penicillin and all were susceptible. Presence or absence of seizures, level of consciousness, Glasgow Coma Score and duration of signs and symptoms were strong predictors of outcome. Collectively no specific safety concerns were identified. CONCLUSION: Cefepime represents an important therapeutic option for the empiric treatment of bacterial meningitis in children, based on the good clinical response and bacteriologic eradication rates observed in this review.

Neonatal sepsis and meningitis in a developing Latin American country.

In a retrospective study at Hospital del Niño in Panama City, Panama, 577 neonates with culture-proved sepsis and/or meningitis were identified during an 18-year period (1975 to 1992). Overall there was an incidence of 3.5 cases/1000 live births. Three hundred thirty-three patients (58%) were of low birth weight (< 2500 g) and 260 (45%) were premature. Gram-negative bacilli, particularly species of Klebsiella and Escherichia coli, were responsible for 61% of infections, whereas Gram-positive isolates (especially staphylococci) and Candida strains accounted for 37 and 2%, respectively. The patterns of predominance among bacterial pathogens, however, changed during the period of study. In the later years of this study the frequency of Gram-negative bacteria declined whereas those of staphylococci and Candida increased. Likewise systemic infections caused by Group B Streptococcus organisms appeared recently. The case-fatality rate was 32%. Mortality was greater in infants with early onset sepsis than in those with late infections (44% vs. 22%, P < 0.0001; odds ratio, 2.8; 95% confidence interval, 1.9 to 4.1) and lesser in neonates infected by coagulase-negative staphylococci than in those infected by any other pathogen (12 vs. 39%, P < 0.001; odds ratio, 0.2; 95% confidence interval, 0.1 to 0.4). These findings provide guidelines for the selection of empiric antimicrobial agents in our country and possibly in other Latin American countries and suggest that a continued thorough epidemiologic evaluation is needed to anticipate bacteriologic changes over time.

Application of new sepsis definitions to evaluate outcome of pediatric patients with severe systemic infections.

No published reports have stratified pediatric patients with systemic infections according to the new sepsis terminology guidelines. In addition little is known about the outcome of sepsis in developing countries. This large 12-year retrospective study evaluated the outcome of 815 infants and children with sepsis managed in a Latin American pediatric intensive care unit. Of these children 171 (21%) had sepsis, 497 (61%) had severe sepsis and 147 (18%) had septic shock. Multiorgan dysfunction was present in 120 (24%) and 77 (52%) patients with severe sepsis and septic shock, respectively. Infection was bacteriologically proved in 212 (26%) cases, with Staphylococcus aureus and Neisseria meningitidis being the most frequent responsible organisms. Three hundred nineteen (39%) patients died. Case-fatality rates were higher in patients with septic shock, multiorgan dysfunction, sepsis caused by Pseudomonas aeruginosa and meningococcemia than in those without these conditions. Although no difference in mortality was detected between culture-proved and culture-negative sepsis, more patients receiving an inappropriate antimicrobial agent died than those treated with an appropriate drug (53% vs. 34%, P = 0.012). We believe that with the use of the new terminology system a more reliable comparison of data from pediatric sepsis studies and of emerging immunomodulating therapeutic modalities can be achieved.

Spiramycin vs. placebo for treatment of acute diarrhea caused by Cryptosporidium.

The efficacy of spiramycin was evaluated in a double blind, placebo-controlled study of 44 immunocompetent infants ages 2 to 13 months who had acute diarrhea caused by Cryptosporidium. Twenty-one patients received spiramycin (100 mg/kg/day) for 10 days and 23 received placebo. On admission the patients in both groups were comparable regarding demographic and clinical characteristics. The infants who were treated with spiramycin had a shorter duration of diarrhea (mean, 5.2 vs. 7.3 days; P = 0.002) and a shorter duration of excretion of oocysts in the stools (7.1 vs. 8.5 days; P = 0.032) compared with those treated with placebo. No clinical or parasitologic relapses were seen in patients of both groups. Mild adverse effects to spiramycin were observed in 2 patients (10%). Spiramycin appeared to hasten clinical recovery and decrease the duration of oocyst excretion in immunocompetent children with diarrheal illness caused by Cryptosporidium.

Impact of an antibiotic restriction policy on hospital expenditures and bacterial susceptibilities: a lesson from a pediatric institution in a developing country.

BACKGROUND: In an era of growing concern about bacterial resistance and hospital costs, limiting the use of broad spectrum antibiotics is important. OBJECTIVES: To evaluate the effects of an antibiotic restriction policy on expenditures, antimicrobial resistance rates and clinical outcomes of hospitalized children. DESIGN: Starting in January, 1997, a prior consultation with an infectious disease specialist for using restricted antibiotics was required in all hospital areas. A retrospective assessment of study objectives obtained 2 years before (1995, 1996) and 2 years after (1997, 1998) initiation of the restriction policy was performed. SETTING: The present study was conducted in a 500-bed university hospital serving children nationwide of a developing country, Panama. RESULTS: Total expenditures for antimicrobial agents decreased by 50%, from $699,543 (US dollars) during 1995 and 1996 to $347,261 during 1997 and 1998. Susceptibility rates of many nosocomial isolates (especially staphylococci and Gram-negative enteric bacilli) usually improved for restricted antibiotics with >35% reduction in utilization (notably for gentamicin, third generation cephalosporins, piperacillin and vancomycin). Major improvements in bacterial susceptibilities were observed in the nursery, a place harboring microorganisms exhibiting the higher initial resistance rates of the hospital. No differences in days of hospital stay and mortality rates of all patients and of children with nosocomial infections were detected during the study period. CONCLUSIONS: Requirement for prior approval of selected antimicrobial drugs in a pediatric institution decreases hospital expenditures and improves susceptibilities to antibiotics without compromising patient outcomes or length of hospital stays.

Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. The MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing. DESIGN: A Phase I/II multicenter, open label, escalating dose clinical trial. PATIENT POPULATION AND DOSING REGIMEN: Children (n=65) born prematurely at < or =35 weeks of gestation who were < or =6 months of age (n=41) and children with bronchopulmonary dysplasia who were < or =24 months of age (n=24) were enrolled. From 1 to 5 monthly injections were given at doses of 5 mg/kg (n=11), 10 mg/kg (n=6) and 15 mg/kg (n=48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay. RESULTS: The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 microg/ml (range, 52.3 to 174.0) 2 days after the initial dose of 15 mg/kg and 49.2 microg/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of approximately 70 microg/ml. These concentrations were similar to previously published trough concentrations after i.v. administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI-493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups. CONCLUSIONS: MEDI-493 was safe and well-tolerated. Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 microg/ml (the value associated with 99% reduction of pulmonary RSV in the cotton rat model). These concentrations were similar to those previously reported with i.v. administration of MEDI-493.

Antimicrobial and anti-inflammatory treatment of bacterial meningitis.

Mortality and morbidity rates of bacterial meningitis are still unacceptably high, and thus, new, potent antimicrobial agents and adjuvant anti-inflammatory strategies are being evaluated to improve patient outcome. With the declining rates of Haemophilus influenzae type B infections, after the introduction of conjugated vaccines, research to find preventive measures for Streptococcus pneumoniae and Neisseria meningitidis infections is underway. In the meantime, scientific effort is being directed optimally to treat disease caused by multiresistant pneumococcal strains.

Bacterial meningitis in neonates and children.

A high index of suspicion of meningitis is needed when evaluating neonates and young infants because clinical findings can be minimal and are often subtle and nonspecific. Analysis of the CSF constitutes the most effective method to document meningeal bacterial infection, although overlap with normal CSF values can occur, especially in newborns and very young infants. The introduction of highly active third-generation cephalosporins (ceftriaxone, cefotaxime) and their safety and efficacy in treating a broad array of bacterial pathogens that cause meningitis in all age groups has simplified selection of initial antibiotic therapy. In neonates, however, conventional antibiotic therapy with ampicillin and an aminoglycoside is appropriate because of its proven record of safety and efficacy, and because routine use of cephalosporins in the hospital nursery could lead to selection of resistant strains among gram-negative enteric bacilli. Despite the availability of modern intensive care management of infants and children with bacterial meningitis and the advent of potent antibiotics, case fatality rates and morbidity remain high. Because of this, recent research has focused on the complex interaction between bacteria and the host and on means to attenuate the meningeal inflammatory response. The clinical benefits demonstrated recently with the use of dexamethasone therapy in infants and children with bacterial meningitis underscore the importance of anti-inflammatory therapy to reduce audiologic and neurologic sequelae. Future studies of new methods to modulate meningeal inflammation such as the use of monoclonal antibodies directed against cytokines or of agents that interfere with leukocyte-endothelial interactions are indicated. The implication of routine H. influenzae type b immunization in young infants with the conjugated vaccines and optimal intrapartum prophylaxis against group B streptococcal disease in newborns will have an important impact on the incidence of meningitis in infants and children.

[Methicillin-resistant Staphylococcus aureus disease in Panama]. / Enfermedad por Staphylococcus aureus resistente a meticilina en Panamá

INTRODUCTION: Infections due to methicillin-resistant Staphylococcus aureus (MRSA) are increasing worldwide. The clinical spectrum of the disease ranges from nasal colonization to superficial and invasive infections. OBJECTIVES: To describe the frequency, clinical characteristics and risk factors associated with MRSA disease in children under 15 years old. To establish the prevalence of colonization and antimicrobial susceptibility of isolates. MATERIAL AND METHODS: Retrospective study. Included subjects; aged 1 month to 15 years old treated in the Hospital del Niño in Panama with invasive or superficial infection by S. aureus in the period from June 1, 2009 to June 30, 2010. Carrier status was assessed by performing nasal swabs. Demographic, clinical features, treatment of disease and antimicrobial resistance patterns. RESULTS: A total of 146 subjects were collected with S.aureus infections, of which 8.9% (13/146) were infected by MRSA. Community-acquired MRSA accounted for 38.5% of the isolates. We did not identify any risk factors for developing MRSA infections. The prevalence of nasal carriage was 8.3%. The resistance rates to erythromycin and clindamycin were 15.4%. CONCLUSIONS: The incidence of MRSA infections was low compared with other regions. We recommend active surveillance in order to establish measures to prevent nosocomial infections and treatment guidelines based on local epidemiological criteria.