Adriano Arguedas

Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis.

Summary Background The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. Methods We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. Findings We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3–13·9 million) episodes of severe and 3·0 million (2·1–4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265u2008000 (95% CI 160u2008000–450u2008000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. Interpretation Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. Funding WHO.

Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media.

Objectives. To determine the bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate (90/6.4 mg/kg/day) against common bacterial pathogens causing acute otitis media (AOM), including penicillin-resistant Streptococcus pneumoniae (PRSP). Methods. In this open label multicenter study, 521 infants and children with AOM [mean age, 18.6 months; age <24 months, n = 375 (72%)] were treated with amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses for 10 days. Bilateral otitis media, previous episodes of AOM, antibiotic treatment within 3 months and day-care attendance were recorded in 60.1, 35.7, 50.2 and 38.2% of the children, respectively. Tympanocentesis was performed before the first dose and repeated on Days 4 to 6 for all children with S. pneumoniae at 22 centers and for all children with any pathogen at 3 centers. Clinical response was assessed at end of therapy. Results. Pathogens were isolated from 355 (68%) of 521 enrolled children; 180 children underwent repeat tympanocentesis and were bacteriologically evaluable. Baseline pathogens were S. pneumoniae (n = 122 enrolled/93 bacteriologically evaluable), Haemophilus influenzae (n = 160/51), both (n = 37/32) and others (n = 36/4). Pathogens were eradicated from 172 (96%) of 180 bacteriologically evaluable children. Overall 122 (98%) of 125 isolates of S. pneumoniae were eradicated, including 31 (91%) of 34 PRSP isolates (penicillin MICs 2 to 4 &mgr;g/ml). Seventy-eight (94%) of 83 isolates of H. influenzae were eradicated. Symptoms and otoscopic signs of acute inflammation were completely resolved or improved on Days 12 to 15 in 263 (89%) of 295 clinically evaluable children with bacteriologically documented AOM. Conclusions. On the basis of bacteriologic outcome on Days 4 to 6 and clinical outcome on Days 12 to 15, we found that high dose amoxicillin/clavulanate (90/6.4 mg/kg/day) was highly efficacious in children with AOM, including those most likely to fail treatment, namely children <24 months of age and those with infections caused by PRSP.

Global serotype distribution among Streptococcus pneumoniae isolates causing otitis media in children: Potential implications for pneumococcal conjugate vaccines

Acute otitis media (AOM) is the most common infection following pneumococcal colonization of the upper respiratory tract. Streptococcus pneumoniae causes 30-60% of AOM cases worldwide. However, not all pneumococcal serotypes cause disease and an association exists with nasopharyngeal colonization by certain serotypes and their propensity to cause AOM. This review examines the global serotype distribution relationship between pneumococcal serotypes and AOM in children aged <18 years and demonstrates that the most common pneumococcal serotypes causing AOM globally are 3, 6A, 6B, 9V, 14, 19A, 19F, and 23F.

Emergence of Penicillin-Nonsusceptible Streptococcus pneumoniae Clones Expressing Serotypes Not Present in the Antipneumococcal Conjugate Vaccine

BACKGROUNDnPenicillin-nonsusceptible Streptococcus pneumoniae isolates are confined mainly to a few serogroups. Capsular transformation may serve as a mechanism for spreading antibiotic resistance to new serotypes.nnnMETHODSnAntibiogram and molecular typing, by pulsed-field gel electrophoresis (PFGE), were performed on 46 nasopharyngeal and middle ear fluid (MEF) isolates expressing serotype 11A, 45 MEF isolates expressing serotype 15B/C (recovered during 1998-2003 from Israeli children <5 years old), and 57 MEF isolates expressing serotype 19F (recovered during 1998-2001 from Costa Rican children <7.5 years old).nnnRESULTSnPFGE patterns showed that 49 (86%) of 57 serotype 19F isolates and 19 (41%) of 46 serotype 15B/C isolates were closely related. The vast majority of these isolates (80% of serotype 19F and 100% of serotype 15B/C isolates) were nonsusceptible to penicillin. Multilocus sequence typing (MLST) data show that the serotype 15B/C isolates belonged to the ST346 cluster, whereas the serotype 19F isolates were a single-locus variant of ST346. For serotype 11A isolates, PFGE patterns and MLST analysis showed that 8 (80%) of the 10 penicillin-nonsusceptible isolates belonged to a single clone--namely, ST156--which was identical to the international Spain9V-3 clone.nnnCONCLUSIONSnPenicillin-nonsusceptible pneumococcal clones of serotypes not related to those included in the 11-valent conjugate vaccines may derive from capsular transformation of vaccine-related serotypes. Of particular concern was the detection of serotype 11A variants of the successful international Spain9V-3 clone. This phenomenon, although seemingly rare at present, can have implications for the long-term effectiveness of the conjugate vaccines.

Safety and Efficacy of Gatifloxacin Therapy for Children with Recurrent Acute Otitis Media (AOM) and/or AOM Treatment Failure

BACKGROUNDnBecause of concerns about arthrotoxicity, fluoroquinolones are restricted for use in children. This study describes the safety and efficacy of gatifloxacin when used for treatment of children with recurrent acute otitis media (ROM) or acute otitis media (AOM) treatment failure (AOMTF).nnnMETHODSnWe performed an analysis of 867 children included in 4 clinical trials who had ROM and/or AOMTF and were treated with gatifloxacin (10 mg/kg once daily for 10 days).nnnRESULTSnGatifloxacin had adverse event rates that were similar overall to those of a comparator antibiotic (amoxicillin-clavulanate), except for increased diarrhea in children <2 years old receiving amoxicillin-clavulanate. There was no evidence of arthrotoxicity, hepatotoxicity, alteration of glucose homeostasis, or central nervous system toxicity acutely or during 1 year follow-up in any child. Regarding efficacy, in 2 noncomparative trials, the gatifloxacin cure rate of AOM was 89% (95% confidence interval [CI], 83%-95%) at the test of cure (TOC) visit, 3-10 days after completion of therapy. In 2 comparative trials of gatifloxacin versus amoxicillin-clavulanate, the efficacy of gatifloxacin was 88% (95% CI, 82%-94%). Gatifloxacin led to better clinical outcomes than amoxicillin-clavulanate for AOMTF (91% vs. 81%; P=.029), for AOMTF and age <2 years old (89% vs. 69%; P=.009), and for severe AOM in children <2 years old (90% vs. 75%; P=.012). Among children with AOMTF previously treated with amoxicillin-clavulanate or ceftriaxone injections, gatifloxacin cure rates were high (88% and 75%, respectively).nnnCONCLUSIONSnGatifloxacin appears to be safe for children, with no evidence of producing arthrotoxicity in 867 children exposed to the antibiotic when used as treatment for ROM and AOMTF.

Otitis media across nine countries: disease burden and management.

OBJECTIVEnTo assess the perceived disease burden and management of otitis media (OM) among an international cohort of experienced physicians.nnnMETHODSnA cross-sectional survey conducted in France, Germany, Spain, Poland, Argentina, Mexico, South Korea, Thailand and Saudi Arabia. Face-to-face interviews conducted with 1800 physicians (95% paediatricians, 5% family practitioners).Main outcome measures were the perceived burden on clinical practice (number of cases, complications and referrals) and first- and second-line management strategies for OM. Results are expressed as mean and range across the nine countries over three continents.nnnRESULTSnRespondents estimated an average annual caseload of 375 (range 128-1003) children under 5 years of age with OM; 54% (range 44-71%) with an initial episode and 38% (range 27-54%) with recurrent OM (ROM). OM with complications was estimated to be approximately 20 (range 7-49) cases per year and an estimated 15% (8-41%) of children with OM was recalled as needing specialist referral. There was high awareness of Streptococcus pneumoniae and Haemophilus influenzae as causative bacterial pathogens: 77% (range 65-91%) and 74% (range 68-83%), respectively, but less recognition of non-typeable H. influenzae (NTHi); 59% (range 45-67%). Although concern over antimicrobial resistance was widespread, empirical treatment with antibiotics was the most common first-line treatment (mean 81%, range 40-96%). The burden of disease is substantial enough that many physicians would consider vaccination to prevent OM (mean score 5.1, range 4.3-6.2 on 1-7 scale).nnnCONCLUSIONSnThis large, multinational survey shows that OM remains a significant burden for clinical practice. Despite awareness of shortcomings, antimicrobial therapy remains the most frequent treatment for OM.

Microbiology of the middle ear fluid in Costa Rican children between 2002 and 2007.

BACKGROUNDnBecause the microbiology and susceptibility patterns of middle ear fluid pathogens in children with otitis media change over time, an active surveillance is recommended to establish appropriate therapeutic guidelines.nnnOBJECTIVEnTo analyze the microbiology and susceptibility pattern of middle ear pathogens obtained from Costa Rican children with acute otitis media (AOM), recurrent otitis media (ROM) and therapeutic failure otitis media (OMTF) between 2002 and 2007.nnnPATIENTS AND METHODSn1108 children aged 2-92 months who participated in various otitis media clinical trials between the years 2002 and 2007.nnnRESULTSnAmong the study population, 880 were children with AOM (61% <24 months of age), 138 were children with ROM (54% <24 months of age) and 90 were children with OMTF (67% <24 months of age). Bilateral otitis media was more frequent in children with OMTF (44%) than in children with AOM (37%) (P=0.19) and ROM (27%) (P=0.009). Presence of siblings <8 years of age was more frequently observed in children with OMTF (73%) than in children with ROM (65%) (P=0.0001) and AOM (47%) (P=0.000002). Overall Streptococcus pneumoniae (44%) was the most common pathogen isolated followed by Haemophilus influenzae (37%), Moraxella catarrhalis (11%) and Streptococcus pyogenes (4%). S. pneumoniae was the most common pathogen in AOM (44%) and ROM (47%), however, H. influenzae was the most common pathogen in OMTF (40%). Among all H. influenzae, an increase in the number of β-lactamase producing strains was observed from 5.2% in 2001 to 14% (P=0.04) in 2007 and this was associated with an increase in the use of amoxicillin. An increase in the number of M. catarrhalis was also observed, from 3% (9/350) in 2001 to 11% (71/628) (P=0.000003) in 2007. During the study period the incidence of penicillin non-susceptible S. pneumoniae was 42/211 (20%) in children with AOM; 5/35 (17%) in children with ROM and 5/17 (42%) in children with OMTF. M. catarrhalis cases increased from 8% in 2004 to 17% in 2007 (P=0.0005) and S. pyogenes decreased from 7% in 2002-2004 to 1% in 2005-2007 (P=0.001).nnnCONCLUSIONSnIn Costa Rica, S. pneumoniae remains the most common pathogen in children with AOM and ROM whereas non-typable H. influenzae remains the most common pathogen in children with OMTF. A significant increase in the number of β-lactamase positive H. influenzae and M. catarrhalis has been observed in recent years.

Streptococcus pneumoniae Serotype 3 among Costa Rican Children with Otitis Media: clinical, epidemiological characteristics and antimicrobial resistance patterns

BackgroundAfter the introduction of the seven valent-pneumococcal conjugated vaccine into our National Immunization Program, it is important to establish and track local serotype distribution in order to evaluate its impact specially because serotype replacement phenomena has been described.To describe the clinical, epidemiological and antimicrobial resistance patterns of Costa Rican children with otitis media caused by Streptococcus pneumoniae serotype 3.MethodsMiddle ear fluid samples were obtained from Costa Rican children with otitis media who participated in various antimicrobial clinical trials between 1992 and 2007. Streptococcus pneumoniae was identified according to laboratory standard procedures. Strains were serotyped and antimicrobial susceptibility to penicillin, amoxicillin, cefuroxime, ceftriaxone, azithromycin and levofloxacin was determined by E-test.ResultsThroughout 1992–2007 a total of 1919 tympanocentesis were performed in children with otitis media (median age: 19 months) and yielded a total of 1208 middle ear isolates. The most common pathogens were: Streptococcus pneumoniae, 511 isolates (49%); Non-Typable Haemophilus influenzae, 386 isolates (37%); Moraxella catarrahalis, 100 isolates (9.5%); and Streptococcus pyogenes, 54 isolates (5%). Streptococcus pneumoniae serotyping was performed in 346/511 isolates (68%) recovered during years 1999–2006. The most common serotypes were 19F (101/30.0%), 14 (46/13.7%), 3 (34/10.1%), 6B (30/8.9%) and 23F (23/6.8%). Analysis performed per years showed a higher prevalence of serotype 3 Streptococcus pneumoniae during the study period 2004 and 2005. During the entire study period (1999–2006) serotype 3 was most commonly isolated in children older than 24 months (61.2% vs 40.6%;P = 0.05) and showed a lower rate of penicillin non-susceptibility (4.0% vs 18%; P = 0.003).ConclusionStreptococcus pneumoniae serotype 3 is an important pathogen in Costa Rican children with otitis media, especially in children older than 24 months of age (P = 0.05). Most serotype 3 isolates were susceptible to penicillin, cephalosporins, macrolides and quinolones.

Pharmacokinetics and Safety of Famciclovir in Children with Herpes Simplex or Varicella-Zoster Virus Infection

ABSTRACT 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 (∼12.5 mg/kg of body weight [BW] for children weighing <40 kg and 500 mg for children weighing ≥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 BW0.696. 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.

Single-dose azithromycin for the treatment of children with acute otitis media

Azithromycin is an azalide with in vitro activity against otitis media pathogens, good middle ear penetration and a prolonged half-life. A total of four clinical trials have evaluated the clinical success rate, safety and compliance of single-dose azithromycin (30 mg/kg) in the treatment of children with otitis media. Among all the patients treated with single-dose azithromycin (30 mg/kg), and presented previously in four published clinical trials, end-of-treatment clinical success was 88% (544 out of 619) and maintained clinical success at the end-of-study was 82% (498 out of 610). Three of the four studies included a mandatory baseline tympanocentesis. The overall end-of-treatment and end-of-study clinical success rates among all culture-positive patients was 84% (222 out of 263) and 80% (210 out of 263), respectively. Per pathogen end-of-treatment clinical success rates observed were 91% (125 out of 137) among patients with Streptococcus pneumoniae, 77% (75 out of 97) among patients with Haemophilus influenzae, 100% (14 out of 14) among patients with Moraxella catarrhalis, 64% (seven out of 11) among patients with baseline Streptococcus pyogenes and 25% (one out of four) among patients with a S. pneumoniae and H. influenzae mixed infection. Clinical success was observed in 90% (106 out of 118) of patients with baseline macrolide-susceptible S. pneumoniae and in 67% (14 out of 21) among patients with baseline macrolide-resistant S. pneumoniae (p = 0.01). Adverse events were uncommon, mostly mild and transitory gastrointestinal complaints, and in the two larger comparative trials, were less frequent than the rates observed with the comparator agents. Compliance was excellent (99–100%). Single-dose azithromycin (30 mg/kg) represents an alternative for the treatment of pediatric patients with uncomplicated acute otitis media, particularly in those geographic regions where high-level S. pneumoniae macrolide resistance is uncommon, and for those patients that require directly observed therapy or when compliance may be a problem.