Etiologies and Resistance Profiles of Bacterial Community-Acquired Pneumonia in Cambodian and Neighboring Countries’ Health Care Settings: A Systematic Review (1995 to 2012)

Community-acquired pneumonia (CAP) is one of the most important causes of morbidity and mortality worldwide. Etiological data for Cambodia is scarce. We aimed to describe the main etiological agents causing CAP, and their resistance patterns in Cambodia and the greater Mekong region.  A review of bacterial etiologies of CAP and antimicrobial resistance in Cambodia and neighboring countries was conducted via: (1) a systematic review of published literature in all NCBI databases using Pubmed, Google scholar, EMBASE, the World Health Organization and the Cambodian Ministry of Health libraries; (2) a review of unpublished data from Cambodia provided by national and international stakeholders working at different tiers of the healthcare system.  Twenty three articles and five data sources reported etiologies for 5919 CAP patients diagnosed between May 1995 and December 2012, including 1421 (24.0%), 3571 (60.3%) and 927 (15.7%) from Cambodia, Thailand and Vietnam, respectively. Streptococcus pneumoniae and Haemophilus influenzae were the most common pathogens ranking among the five most prevalent in 12 and 10 studies, respectively. Gram-negative bacteria such as Burkholderia pseudomallei and Klebsiella pneumoniae were also frequently diagnosed, particularly in bacteremic CAP in Thai adults and Cambodian children. In Thailand and Vietnam, Mycoplasma pneumoniae and Chlamydia pneumoniae were frequently identified in settings using indirect laboratory testing.  Based on this analysis, CAP data in Cambodia seems to present etiological and resistance profiles comparable to those of neighboring countries. Findings have been shared with the national authorities upon the revision of the national therapeutic guidelines and were disseminated using a specially created website.

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We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions.



In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted.



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Bill & Melinda Gates Foundation.

title: Global, regional, and national causes of child mortality in 2008: a systematic analysis
abstract: Up-to-date information on the causes of child deaths is crucial to guide global efforts to improve child survival. We report new estimates for 2008 of the major causes of death in children younger than 5 years.



We used multicause proportionate mortality models to estimate deaths in neonates aged 0-27 days and children aged 1-59 months, and selected single-cause disease models and analysis of vital registration data when available to estimate causes of child deaths. New data from China and India permitted national data to be used for these countries instead of predictions based on global statistical models, as was done previously. We estimated proportional causes of death for 193 countries, and by application of these proportions to the country-specific mortality rates in children younger than 5 years and birth rates, the numbers of deaths by cause were calculated for countries, regions, and the world.



Of the estimated 8.795 million deaths in children younger than 5 years worldwide in 2008, infectious diseases caused 68% (5.970 million), with the largest percentages due to pneumonia (18%, 1.575 million, uncertainty range [UR] 1.046 million-1.874 million), diarrhoea (15%, 1.336 million, 0.822 million-2.004 million), and malaria (8%, 0.732 million, 0.601 million-0.851 million). 41% (3.575 million) of deaths occurred in neonates, and the most important single causes were preterm birth complications (12%, 1.033 million, UR 0.717 million-1.216 million), birth asphyxia (9%, 0.814 million, 0.563 million-0.997 million), sepsis (6%, 0.521 million, 0.356 million-0.735 million), and pneumonia (4%, 0.386 million, 0.264 million-0.545 million). 49% (4.294 million) of child deaths occurred in five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan, and China.



These country-specific estimates of the major causes of child deaths should help to focus national programmes and donor assistance. Achievement of Millennium Development Goal 4, to reduce child mortality by two-thirds, is only possible if the high numbers of deaths are addressed by maternal, newborn, and child health interventions.

title: Global burden of disease in young people aged 10–24 years: a systematic analysis
abstract: Young people aged 10-24 years represent 27% of the world's population. Although important health problems and risk factors for disease in later life emerge in these years, the contribution to the global burden of disease is unknown. We describe the global burden of disease arising in young people and the contribution of risk factors to that burden.



We used data from WHO's 2004 Global Burden of Disease study. Cause-specific disability-adjusted life-years (DALYs) for young people aged 10-24 years were estimated by WHO region on the basis of available data for incidence, prevalence, severity, and mortality. WHO member states were classified into low-income, middle-income, and high-income countries, and into WHO regions. We estimated DALYs attributable to specific global health risk factors using the comparative risk assessment method. DALYs were divided into years of life lost because of premature mortality (YLLs) and years lost because of disability (YLDs), and are presented for regions by sex and by 5-year age groups.



The total number of incident DALYs in those aged 10-24 years was about 236 million, representing 15·5% of total DALYs for all age groups. Africa had the highest rate of DALYs for this age group, which was 2·5 times greater than in high-income countries (208 vs 82 DALYs per 1000 population). Across regions, DALY rates were 12% higher in girls than in boys between 15 and 19 years (137 vs 153). Worldwide, the three main causes of YLDs for 10-24-year-olds were neuropsychiatric disorders (45%), unintentional injuries (12%), and infectious and parasitic diseases (10%). The main risk factors for incident DALYs in 10-24-year-olds were alcohol (7% of DALYs), unsafe sex (4%), iron deficiency (3%), lack of contraception (2%), and illicit drug use (2%).



The health of young people has been largely neglected in global public health because this age group is perceived as healthy. However, opportunities for prevention of disease and injury in this age group are not fully exploited. The findings from this study suggest that adolescent health would benefit from increased public health attention.

title: Clinical and economic burden of community-acquired pneumonia amongst adults in the Asia-Pacific region.
abstract: Community-acquired pneumonia (CAP) is an important cause of mortality and morbidity amongst adults in the Asia-Pacific region. Literature published between 1990 and May 2010 on the clinical and economic burden of CAP amongst adults in this region was reviewed. CAP is a significant health burden with significant economic impact in this region. Chronic obstructive pulmonary disease, cardiovascular disease, diabetes mellitus and advanced age were risk factors for CAP. Aetiological agents included Streptococcus pneumoniae, Klebsiella pneumoniae, Gram-negative bacteria, Mycobacterium tuberculosis, Burkholderia pseudomallei, Staphylococcus aureus and atypical pathogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella spp.), with important differences in the prevalence of these pathogens within the region. Antibiotic resistance was significant but was not linked to excess mortality. Aetiological pathogens remained susceptible to newer antimicrobial agents. Rational antibiotic use is essential for preventing resistance, and increased surveillance is required to identify future trends in incidence and aetiology and to drive treatment and prevention strategies.

title: Management of community-acquired pneumonia: a review and update
abstract: Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide, affecting approximately 5.6 million patients annually in the USA, where the annual cost exceeds US$12 billion. Optimal management should be based on knowledge of the most likely etiologic pathogens for each patient, based on an assessment of specific risk factors. It is also essential to assess severity of illness, to determine the appropriate site of care, and to order appropriate diagnostic testing. New developments in CAP management have focused on recognizing newly identified pathogens, such as methicillin-resistant Staphylococcus aureus and novel H1N1 influenza, understanding when to utilize new microbiological diagnostic techniques, and how to use biomarkers to direct the appropriate utilization of antibiotics and to define the duration of therapy. This paper reviews recent advances in our knowledge about the diagnosis and optimal management of CAP.

title: Setting Research Priorities to Reduce Global Mortality from Childhood Pneumonia by 2015
abstract: Igor Rudan and colleagues report the results of their consensus building exercise that identified health research priorities to help reduce child mortality from pneumonia.

title: Diagnosing pneumonia in patients with acute cough: clinical judgment compared to chest radiography
abstract: Pneumonia is often diagnosed and treated empirically. We set out to determine the diagnostic accuracy of clinical judgment based on signs and symptoms to detect radiographic pneumonia in patients presenting with acute cough in primary care. In 2810 European patients with acute cough, general practitioners (GPs) recorded whether they considered pneumonia to be present (“yes” or “no”) immediately after history and physical examination. Chest radiography was performed within 1 week by local radiologists blind to other patient characteristics. 140 patients had radiographic pneumonia (5%), of whom 41 (29%) had been diagnosed as such. 31 (1%) patients had a clinical diagnosis that was not confirmed by radiography (n=2670). In clinically suspected pneumonia, 57% of subjects were subsequently diagnosed with radiographic pneumonia. Negative predictive value (NPV), sensitivity and specificity of GPs’ clinical judgment were 96%, 29% and 99%, respectively. Compared to patients with a clinical diagnosis of pneumonia, less severe symptoms were found in radiographic pneumonia cases not suspected clinically (p<0.05). The predictive values of GPs’ clinical judgment, particularly the high NPVs, are helpful in routine care. Nonetheless, the majority of diagnoses of radiographic pneumonias was not suspected on clinical grounds. There is a need to further support the detection of clinically relevant pneumonia in primary care. There is a need to further support the detection of clinically relevant pneumonia in primary care http://ow.ly/mxw6Z

title: Can an etiologic agent be identified in adults who are hospitalized for community-acquired pneumonia: Results of a one-year study
abstract: Determining the cause of community-acquired pneumonia (CAP) remains problematic. In this observational study, we systematically applied currently approved diagnostic techniques in patients hospitalized for CAP in order to determine the proportion in which an etiological agent could be identified.
               
               
                  Methods
                  All patients admitted with findings consistent with CAP were included. Sputum and blood cultures, urine tests for pneumococcal and Legionella antigens, nasopharyngeal swab for viral PCR, and serum procalcitonin were obtained in nearly every case. Admission-related electronic medical records were reviewed in entirety.
               
               
                  Results
                  By final clinical diagnosis, 44 patients (17.0%) were uninfected. A causative bacterium was identified in only 60 (23.2%) cases. PCR identified a respiratory virus in 42 (16.2%), 12 with documented bacterial coinfection. In 119 (45.9%), no cause for CAP was found; 69 (26.6%) of these had a syndrome indistinguishable from bacterial pneumonia. Procalcitonin was elevated in patients with bacterial infection and low in uninfected patients or those with viral infection, but with substantial overlap.
               
               
                  Conclusions
                  Only 23.2% of 259 patients admitted with a CAP syndrome had documented bacterial infection; another 26.6% had no identified bacterial etiology, but findings closely resembled those of bacterial infection. Nevertheless, all 259 received antibacterial therapy. Careful attention to the clinical picture may identify uninfected patients or those with viral infection, perhaps with reassurance by a non-elevated procalcitonin. Determining an etiologic diagnosis remains elusive. Better discriminators of bacterial infection are sorely needed.

title: Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults
abstract: Lionel A. Mandell, Richard G. Wunderink, Antonio Anzueto, John G. Bartlett, G. Douglas Campbell, Nathan C. Dean, Scott F. Dowell, Thomas M. File, Jr. Daniel M. Musher, Michael S. Niederman, Antonio Torres, and Cynthia G. Whitney McMaster University Medical School, Hamilton, Ontario, Canada; Northwestern University Feinberg School of Medicine, Chicago, Illinois; University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, and Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas; Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi School of Medicine, Jackson; Division of Pulmonary and Critical Care Medicine, LDS Hospital, and University of Utah, Salt Lake City, Utah; Centers for Disease Control and Prevention, Atlanta, Georgia; Northeastern Ohio Universities College of Medicine, Rootstown, and Summa Health System, Akron, Ohio; State University of New York at Stony Brook, Stony Brook, and Department of Medicine, Winthrop University Hospital, Mineola, New York; and Cap de Servei de Pneumologia i Allergia Respiratoria, Institut Clinic del Torax, Hospital Clinic de Barcelona, Facultat de Medicina, Universitat de Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, CIBER CB06/06/0028, Barcelona, Spain.

title: Epidemiological impact of mass tuberculosis screening: a 2-year follow-up after a national prevalence survey.
abstract: To assess the epidemiological impact of mass tuberculosis (TB) screening in the community and the prognosis of bacteriologically negative individuals with abnormal findings on chest radiography (CXR).



A follow-up study consisting of two parts--a register match of notified TB cases with 22,160 participants in a national TB prevalence survey, and a repeat medical examination for the subjects of a prevalence survey with abnormal findings on CXR--was conducted 2 years after the prevalence survey in Cambodia.



Thirty-four cases with new smear-positive TB were detected by register match, giving a standardised notification ratio of 0.38 (95%CI 0.27-0.52). An additional seven new smear-positive TB cases and 93 new smear-negative, culture-positive TB cases were detected by medical examination. The incidence rates of bacteriologically positive TB were 8.5% per year (95%CI 6.3-11.2) in cases with a CXR suggestive of active TB and 2.9% per year (95%CI 2.2-3.7) in those with a CXR with other abnormalities.



Detection and treatment of smear-negative, culture-positive TB cases as well as smear-positive TB cases was associated with a rapid reduction in subsequent incidence of new smear-positive TB. Sputum culture-negative individuals with abnormal CXR findings are at a high risk of disease progression, and require follow-up and potentially preventive treatment.

title: Early detection of tuberculosis through community-based active case finding in Cambodia
abstract: BackgroundSince 2005, Cambodia’s national tuberculosis programme has been conducting active case finding (ACF) with mobile radiography units, targeting household contacts of TB patients in poor and vulnerable communities in addition to routine passive case finding (PCF). This paper examines the differences in the demographic characteristics, smear grades, and treatment outcomes of pulmonary TB cases detected through both active and passive case finding to determine if ACF could contribute to early case finding, considering associated project costs for ACF.MethodsDemographic characteristics, smear grades, and treatment outcomes were compared between actively (n = 405) and passively (n = 602) detected patients by reviewing the existing programme records (including TB registers) of 2009 and 2010. Additional analyses were performed for PCF cases detected after the ACF sessions (n = 91).ResultsThe overall cost per case detected through ACF was US$ 108. The ACF approach detected patients from older populations (median age of 55 years) compared to PCF (median age of 48 years; p < 0.001). The percentage of smear-negative TB cases detected through ACF was significantly higher (71.4%) than that of PCF (40.5%). Among smear-positive patients, lower smear grades were observed in the ACF group compared to the PCF group (p = 0.002). A fairly low initial defaulter rate (21 patients, 5.2%) was observed in the ACF group. Once treatment was initiated, high treatment success rates were achieved with 96.4% in ACF and with 95.2% in PCF. After the ACF session, the smear grade of TB patients detected through routine PCF continued to be low, suggesting increased awareness and early case detection.ConclusionsThe community-based ACF in Cambodia was found to be a cost-effective activity that is likely to have additional benefits such as contribution to early case finding and detection of patients from a vulnerable age group, possibly with an extended benefit for reducing secondary cases in the community. Further investigations are required to clarify the primary benefits of ACF in early and increased case detection and to assess its secondary impact on reducing on-going transmission.

title: Klebsiella pneumoniae related community-acquired acute lower respiratory infections in CAMBODIA: clinical characteristics and treatment
abstract: In many Asian countries, Klebsiella pneumoniae (KP) is the second pathogen responsible for community-acquired pneumonia. Yet, very little is known about KP etiology in ALRI in Cambodia, a country that has one of the weakest medical infrastructures in the region. We present here the first clinico-radiological description of KP community-acquired ALRI in hospitalized Cambodian patients.  Through ALRI surveillance in two provincial hospitals, KP was isolated from sputum and blood cultures, and identified by API20E gallery from patients ≥ 5 years-old with fever and respiratory symptoms onset ≤14 days. Antibiotics susceptibility testing was provided systematically to clinicians when bacteria were isolated. We collected patients’ clinical, radiological and microbiological data and their outcome 3 months after discharge. We also compared KP-related with other bacteria-related ALRI to determine risk factors for KP infection.  From April 2007 to December 2009, 2315 ALRI patients ≥ 5 years-old were enrolled including 587 whose bacterial etiology could be assigned. Of these, 47 (8.0%) had KP infection; their median age was 55 years and 68.1% were females. Reported prior medication was high (42.5%). Patients’ chest radiographs showed pneumonia (61.3% including 39% that were necrotizing), preexisting parenchyma lesions (29.5%) and pleural effusions alone (4.5%) and normal parenchyma (4.5%). Five patients had severe conditions on admission and one patient died during hospitalization. Of the 39 patients that were hospital discharged, 14 died including 12 within 1 month after discharge. Only 13 patients (28%) received an appropriate antibiotherapy. Extended-spectrum beta-lactamases (ESBL) - producing strains were found in 8 (17.0%) patients. Female gender (Odds ratio (OR) 2.1; p = 0.04) and diabetes mellitus (OR 3.1; p = 0.03) were independent risk factors for KP-related ALRI.  KP ALRI in Cambodia has high fatality rate, are more frequently found in women, and should be considered in diabetic patients. The extremely high frequency of ESBL-producing strains in the study is alarming in the context of uncontrolled antibiotic consumption and in absence of microbiology capacity in most public-sector hospitals.

title: Epidemiology of community-acquired pneumonia in children of Latin America and the Caribbean: a systematic review and meta-analysis.
abstract: This systematic review evaluated the incidence, etiology, and use of resources in bacterial, non-tuberculosis community-acquired pneumonia (CAP) in immune-competent children aged <5 years.



Systematic searches (1980-2008) were performed using MEDLINE, Cochrane Library, EMBASE, LILACS, generic, and academic Internet searches. Regional health ministries, the Pan American Health Organization (PAHO), regional proceedings, doctoral theses, and the reference lists of included studies were also searched, and experts were consulted. Arcsine transformations and the DerSimonian-Laird random-effects model were used for proportion meta-analyses.



The search yielded 1220 references; 60 were included in the meta-analysis, giving a total 23 854 CAP episodes with an incidence of 919/100 000 child-years in children aged <5 years. Streptococcus pneumoniae was the most frequently isolated agent (11.08%; 95% confidence interval (CI) 7.63-15.08), and pneumococcal serotype 14 was most prevalent (33.00%; 95% CI 25.95-40.45). Other common agents were Haemophilus influenzae and Mycoplasma pneumoniae. Health economics data on CAP in the region were scarce. About one-fourth of CAP patients required hospitalization (median length of stay 11 days, range 5-13.5 days).



The burden of CAP was substantial, with S. pneumoniae, H. influenzae, and M. pneumoniae being the most common pathogens identified. High quality primary studies on disease incidence, use of health resources, and standardized data collection on disease burden and circulating strains are essential to provide baseline data for the future evaluation of vaccine impact.

title: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies.
abstract: Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. 18 items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the Web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.

title: Prevalence of Chlamydia pneumoniae infection in Thai children with community-acquired pneumonia
abstract: The prevalence of Chlamydia pneumoniae infection in children with community-acquired pneumonia was investigated at Chulalongkorn Hospital, Bangkok from 1999 through 2001. Serologic evidence of acute C. pneumoniae infection was found in 149 of 333 (44.7%) children, of whom 132 of 149 (88%) were <5 years of age. The findings provide further evidence that C. pneumoniae infection is common in very young children.

title: Emergence of Pediatric Melioidosis in Siem Reap, Cambodia
abstract: We describe the first cases of pediatric melioidosis in Cambodia. Thirty-nine cases were diagnosed at the Angkor Hospital for Children, Siem Reap, between October 2005 and December 2008 after the introduction of microbiology capabilities. Median age was 7.8 years (range = 1.6–16.2 years), 15 cases were male (38%), and 4 cases had pre-existing conditions that may have pre-disposed the patient to melioidosis. Infection was localized in 27 cases (69%) and disseminated in 12 cases (31%). Eleven cases (28%) were treated as outpatients, and 28 (72%) cases were admitted. Eight children (21%) died a median of 2 days after admission; seven deaths were attributable to melioidosis, all of which occurred in children receiving suboptimal antimicrobial therapy and before bacteriological culture results were available. Our findings indicate the need for heightened awareness of melioidosis in Cambodia, and they have led us to review microbiology procedures and antimicrobial prescribing of suspected and confirmed cases.

title: Clinical study concerning the relationship between community-acquired pneumonia and viral infection in northern Thailand.
abstract: The etiological agents associated with community-acquired pneumonia (CAP) in Thailand have been studied extensively in bacterial pathogens, but not in viral pathogens. To clarify the association of viral pathogens with CAP, we conducted a comprehensive study of viral and bacterial pathogens in patients with CAP.



We enrolled 119 hospitalized patients with CAP in Nakornping Hospital, Chiang Mai, Thailand between 2006 and 2008. The severity of pneumonia was classified and the risk factors for death were estimated. Bacterial and fungal pathogens were determined from specimens taken from blood and sputum, and viral pathogens were identified from nasopharyngeal specimens by RT-PCR using primers specific for 7 respiratory viruses.



Overall, 29 patients were HIV-infected and 90 patients were non-HIV-infected. The microbial pathogens most commonly isolated among HIV-infected patients were: 4 Klebsiella pneumoniae, 4 Mycobacterium tuberculosis and 3 Haemophilus influenzae. Among non-HIV infected patients, predominant microbial pathogens were: 6 Pseudomonas aeruginosa, 5 Haemophilus influenzae and 4 Klebsiella pneumoniae. As for viral pathogens for CAP, influenza virus was identified from 2 HIV-infected patients and 5 non-HIV infected patients. In addition, human rhinovirus (HRV) and respiratory syncytial virus (RSV) were identified from 2 patients each among non-HIV-infected patients.



Our study demonstrates that the most common viral agent was influenza virus (5%), followed by HRV (2%) and RSV (2%) among CAP patients in northern Thailand. The underlying chronic obstructive pulmonary disease (COPD) seems to be correlated with the severity of illness.

title: Mycoplasma pneumoniae and Chlamydophila pneumoniae in children with community-acquired pneumonia in Thailand.
abstract: The prevalence of community-acquired pneumonia (CAP) caused by atypical pathogens in Thai children is unknown.



To examine the prevalence of Mycoplasma pneumoniae and Chlamydophila pneumoniae infections in paediatric patients (aged 2-15 years) with CAP in three academic hospitals using standardised laboratory techniques. The characteristics of atypical pneumonia were also compared with other causes of CAP.



Diagnosis of current infection was based on a four-fold or more rise in antibody serum samples or persistently high antibody titres together with the presence of mycoplasmal or chlamydial DNA in secretions.



Of 245 patients with CAP, 17.5% of cases were caused by atypical pathogens (M. pneumoniae 14.3%, C. pneumoniae 2.8% and co-infection 0.4%). We also found atypical pathogens in young children aged 2-5 years. The clinical and laboratory findings did not distinguish atypical pneumonia from other CAPs. Segmental or lobar consolidation on chest X-rays was more common in atypical pneumonia, while dyspnoea was more prominent in other CAPs.



Our data show a high prevalence of M. pneumoniae and C. pneumoniae in Thai children with CAP, including in children aged 2-5 years.

title: The incidence of pneumonia in rural Thailand☆
abstract: Pneumonia continues to be a leading infectious disease killer, yet accurately measuring incidence remains a challenge. In 2002, Thailand began active, population-based surveillance for radiographically confirmed pneumonia in Sa Kaeo Province.
               
               
                  Methods
                  Full-time surveillance officers conducted active case ascertainment at every hospital, and routine audits and a community cluster survey promoted complete and accurate reporting. A case of pneumonia was defined as acute infection with signs or symptoms of lower respiratory tract infection and evidence of new infiltrates. An independent panel of radiologists reviewed digital images of all radiographs.
               
               
                  Results
                  Between September 2002 and August 2003, 777 patients met the case definition. The measured minimum incidence was 177/100000 but the estimated incidence was as high as 580/100000 with full adjustment for incomplete chest radiography and access to health care. Seventy-two (9%) patients died and 28% were known to be HIV positive. Fifteen (2%) patients had pneumonia twice during the year. The average cost of hospitalization for an episode of pneumonia ranged from US$490.80 to $628.60.
               
               
                  Conclusions
                  Pneumonia is a significant and costly public health problem in Thailand. This surveillance system allows precise assessment and monitoring of radiologically confirmed pneumonia and lays the groundwork for the introduction of new vaccines against pneumonia pathogens.

title: Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand
abstract: Although pneumonia is a leading cause of death from infectious disease worldwide, comprehensive information about its causes and incidence in low- and middle-income countries is lacking. Active surveillance of hospitalized patients with pneumonia is ongoing in Thailand. Consenting patients are tested for seven bacterial and 14 viral respiratory pathogens by PCR and viral culture on nasopharyngeal swab specimens, serology on acute/convalescent sera, sputum smears and antigen detection tests on urine. Between September 2003 and December 2005, there were 1730 episodes of radiographically confirmed pneumonia (34·6% in children aged <5 years); 66 patients (3·8%) died. A recognized pathogen was identified in 42·5% of episodes. Respiratory syncytial virus (RSV) infection was associated with 16·7% of all pneumonias, 41·2% in children. The viral pathogen with the highest incidence in children aged <5 years was RSV (417·1/100 000 per year) and in persons aged ⩾50 years, influenza virus A (38·8/100 000 per year). These data can help guide health policy towards effective prevention strategies.

title: Epidemiology of severe pneumonia caused by Legionella longbeachae, Mycoplasma pneumoniae, and Chlamydia pneumoniae: 1-year, population-based surveillance for severe pneumonia in Thailand.
abstract: Legionella species, Mycoplasma pneumoniae, and Chlamydia pneumoniae are recognized as important causes of pneumonia in high-income countries, but their significance in middle-income countries, such as Thailand, is unknown.



Population-based surveillance identified inpatient 3489 cases of clinically-defined pneumonia in a rural Thai province for 1 year. Patients who had a chest radiograph performed (for 2059 cases of pneumonia) were enrolled in an etiology study (which included 755 cases of pneumonia among 738 patients). Paired serum, nasopharyngeal swab, and urine specimens were obtained for diagnostic immunologic and molecular tests. Patients aged <18 years were not systematically tested for Legionella species. We report a lower limit of incidence (observed incidence) and an upper limit extrapolated to persons not tested or not enrolled in the study.



The incidence of pneumonia due to Legionella longbeachae requiring hospitalization was 5-29 cases per 100,000 population. No case of Legionella pneumophila pneumonia was observed. The definite C. pneumoniae pneumonia incidence was 3-23 cases per 100,000 population; rates were highest among patients aged <1 year (18-166 cases per 100,000 population) and those aged >or=70 years (23-201 cases per 100,000 population). M. pneumoniae pneumonia had a similar age distribution, with an overall incidence of 6-44 cases per 100,000 population. These pathogens were associated with 15% of all cases of pneumonia. A nonsignificantly higher proportion of patients with pneumonia associated with L. longbeachae, compared with patients with pneumonia associated with M. pneumoniae or C. pneumoniae, required supplemental oxygen or mechanical ventilation (45% vs. 18%; P<.1). Among patients with atypical pneumonia, only 15% received antibiotics with activity against the associated pathogen.



M. pneumoniae, C. pneumoniae, and L. longbeachae, but not L. pneumophila, are frequently associated with severe pneumonia in rural Thailand. Few patients receive antibiotics that cover atypical pathogens.

title: Epidemiology of radiographically-confirmed and bacteremic pneumonia in rural Thailand.
abstract: Pneumonia remains a leading public health concern in Thailand. Using population-based surveillance during January 2004-December 2006, we describe incidence, mortality, and bacterial etiologies of chest radiograph-confirmed pneumonia requiring hospitalization in one rural Thai province. Of 19,316 patients who met the case definition for clinical pneumonia, 9,596 (50%) had a chest radiograph, and 4,993 (52%) of those had radiographically-confirmed pneumonia. The incidence of radiographically-confirmed pneumonia ranged from 199 to 256 per 100,000 persons per year; 151 (3.0%) patients died. The annual average pneumonia mortality rate was 6.9 per 100,000 persons (range 6.2 to 7.8 per 100,000) and was highest in persons aged < 1 year (64/100,000) and > or = 65 years (44/100,000). Of 4,993 patients with radiographically-confirmed pneumonia, 1,916 (38%) had blood cultures, and 187 (10%) of those had pathogens isolated. Pathogens causing bacteremic pneumonia included B. pseudomallei (15% to 24% of bacterial pathogens), E. coli (9.2% to 25%), S. pneumoniae (7.9% to 17%), K. pneumoniae (2.2% to 6.4%), and S. aureus (4.3 to 5.3%). Bacteremia was significantly associated with pneumonia mortality after controlling for age, sex, HIV status and measures of disease severity in a logistic regression model (OR=5.2; 95% confidence interval= 2.2-12). Pneumonia remains an important cause of morbidity and mortality in Thailand, as in other countries in Southeast Asia. These findings can inform pneumonia clinical management and treatment decisions and guide public health programming, including the development of effective prevention strategies.

title: Prevalence of Mycoplasma and Chlamydia pneumonia in severe community-acquired pneumonia among hospitalized children in Thailand.
abstract: Pneumonia is the leading cause of pediatric morbidity and mortality worldwide, and Mycoplasma pneumoniae and Chlamydia pneumoniae are the two most common atypical pathogens. This study was designed to determine the prevalence and clinical impact of mycoplasma and chlamydia pneumonia in children hospitalized with severe pneumonia. Children 1 month-15 years old with a diagnosis of severe pneumonia (WHO criteria) were recruited between March 2005 and March 2006. Serologic studies were performed for anti-M. pneumoniae and anti-C. pneumoniae IgG/M on admission and 2-4 weeks afterward using ELISA. Of 52 patients, 13 (25%) were positive for Mycoplasma, 8 (15%) were positive for Chlamydia, 4 (7.6%) were positive for a mixed infection and 27 (52%) were negative. The subjects' mean age was 23.8+/-4.1 months. The mean of initial oxygen saturation on admission was 87.5+/-1.2%. Fever and prolonged cough were the leading symptoms. The mean of hospitalization was 18.8+/-2.6 days, chlamydia pneumonia had the longest duration, 30+/-10.2 days and 13/52 (25%) study subjects developed respiratory failure. Only 10% were treated with adequate antibiotic prior to serologic results. There was one mortality (1/52, 2%). Our study suggests that mycoplasma and chlamydia infections are commonly found among children hospitalized with severe pneumonia. Coverage with an appropriate antibiotic should be considered to hasten recovery.

title: Epidemiology and clinical outcomes of community-acquired pneumonia in adult patients in Asian countries: a prospective study by the Asian network for surveillance of resistant pathogens
abstract: Abstract
 
 Appropriate antimicrobial treatment of community-acquired pneumonia (CAP) should be based on the distribution of aetiological pathogens, antimicrobial resistance of major pathogens, clinical characteristics and outcomes. We performed a prospective observational study of 955 cases of adult CAP in 14 hospitals in eight Asian countries. Microbiological evaluation to determine etiological pathogens as well as clinical evaluation was performed. Bronchopulmonary disease (29.9%) was the most frequent underlying disease, followed by cardiovascular diseases (19.9%), malignancy (11.7%) and neurological disorder (8.2%). Streptococcus pneumoniae (29.2%) was the most common isolate, followed by Klebsiella pneumoniae (15.4%) and Haemophilus influenzae (15.1%). Serological tests were positive for Mycoplasma pneumoniae (11.0%) and Chlamydia pneumoniae (13.4%). Only 1.1% was positive for Legionella pneumophila by urinary antigen test. Of the pneumococcal isolates, 56.1% were resistant to erythromycin and 52.6% were not susceptible to penicillin. Seventeen percent of CAP had mixed infection, especially S. pneumoniae with C. pneumoniae. The overall mortality rate was 7.3%, and nursing home residence, mechanical ventilation, malignancy, cardiovascular diseases, respiratory rate>30/min and hyponatraemia were significant independent risk factors for mortality by multivariate analysis (P
 <0.05). The current data provide relevant information about pathogen distribution and antimicrobial resistance of major pathogens of CAP as well as clinical outcomes of illness in Asian countries.

title: The etiology of bacterial pneumonia and meningitis in Vietnam.
abstract: To date no studies on the incidence of Haemophilus influenzae type b (Hib) disease, Hib carrier rates in infants and children or the proportion of bacterial meningitis cases caused by Hib in Vietnam have been performed. The availability of safe and highly effective Hib vaccines makes such information important.



The bacterial etiology of a sample of infants and children with pneumonia and meningitis seen at Pediatric Hospital No. 1 in Ho Chi Minh City was studied by culture and latex agglutination of blood, cerebrospinal fluid, urine and pleural fluid. The carriage rate of pneumococci and Hib was studied in a sample of outpatient children.



Hib caused 53% of 34 culture-proven bacterial meningitis cases and pneumococci caused 18%. Of 31 meningitis cases diagnosed by latex agglutination, 39% were caused by Hib and 55% by pneumococci. Ninety percent of cases of Hib meningitis occurred in children <1 year of age. Fifty percent of meningitis cases were associated with acute respiratory infection. In 213 bacteremic pneumonia cases 92.5% of blood cultures grew Streptococcus pneumoniae and only 1% grew Hib. The carrier rate of Hib in outpatients <5 years of age with upper respiratory tract infection increased from 2% to 7.6% between 1993 and 1996.



Hib is the most frequent cause of meningitis in infants and children admitted to hospitals in South Vietnam. Ninety percent of Hib meningitis cases occur in patients < 1 year of age. Bacteremic Hib pneumonia in Vietnam is rare. The results suggest that Hib is the major cause of meningitis in Vietnam but do not permit conclusions regarding its true incidence. The carrier rate of Hib in children <5 years of age in Vietnam has increased to approximately 7% since 1993.

title: Association Between Nasopharyngeal Load of Streptococcus pneumoniae, Viral Coinfection, and Radiologically Confirmed Pneumonia in Vietnamese Children
abstract: The interplay between nasopharyngeal bacterial carriage, viral coinfection, and lower respiratory tract infections (LRTIs) is poorly understood. We explored this association in Vietnamese children aged less than 5 years.  A hospital-based case-control study of pediatric LRTIs was conducted in Nha Trang, Vietnam. A total of 550 hospitalized children (274 radiologically confirmed pneumonia [RCP] and 276 other LRTIs) were enrolled and 350 healthy controls were randomly selected from the community. Polymerase chain reaction-based methods were used to measure bacterial loads of Streptococcus pneumoniae (SP), Haemophilus influenzae, and Moraxella catarrhalis and to detect 13 respiratory viruses and bacterial serotypes in nasopharyngeal samples of study participants.  The median nasopharyngeal bacterial load of SP was substantially higher in children with RCP compared with healthy controls or children with other LRTIs (P < 0.001). SP load was 15-fold higher in pneumonia children with viral coinfection compared with those children without viral coinfection (1.4 × 107/mL vs. 9.1 × 105/mL; P = 0.0001). SP load was over 200-fold higher in serotypeable SP compared with nontypeable SP (2.5 × 106/mL vs. 1 × 104/mL; P < 0.0001). These associations were independent of potential confounders in multiple regression models. No clear association was found between nasopharyngeal load of Haemophilus influenzae or Moraxella catarrhalis and viral coinfection in either RCP or other LRTIs groups.  An increased load of SP in the nasopharynx was associated with RCP, viral coinfection, and presence of pneumococcal capsule.

title: Clinical and microbiological characteristics of community-acquired pneumonia among human immunodeficiency virus-infected patients in northern Thailand
abstract: Human immunodeficiency virus (HIV) infections are prevalent in Thailand. However, the clinical and microbiological characteristics of community-acquired pneumonia (CAP) in such patients are not completely clear at present. In the present study, we analyzed the characteristics of CAP in 191 HIV-infected patients (192 episodes, 130 males and 61 females, mean age 32.9 years, range: 20–62) who had been admitted to Nakornping Hospital in northern Thailand between December 1996 and January 2002. The mean peripheral blood CD4 lymphocyte count was 68.5/mm3 (range: 0–791). The most common organisms detected in the blood of the subjects were as follows: Penicillium marneffei, 13, Salmonella spp., 5, Cryptococcus neoformans, 4, Staphylococcus aureus, 3, and Rhodococcus equi, 3, and the most common organisms detected in sputum included Haemophilus influenzae, 38, P. marneffei, 10, Streptococcus pneumoniae, 10, R. equi, 9, and S. aureus, 9. Life-threatening meningitis in 5 (cryptococcal in 3 and tuberculous in 2), pneumothorax in 2, and tuberculous lymphadenitis in 1 were also noted, resulting in 21 fatalities (10.9%). The mean peripheral blood CD4 lymphocyte count for cases in which the subject died was 74.8/mm3 (range: 0–340). Logistic regression analysis demonstrated that high age (odds ratio of over 40 years: 15.62) and R. equi infection (odds ratio: 8.14) are related to death of HIV-infected patients with CAP. The above findings indicate that various types of organisms, including mixed organisms, cause CAP in HIV-infected patients in northern Thailand, and high age and R. equi infection seem to be risk factors for death.

title: Antimicrobial susceptibility of Streptococcus pneumoniae isolated from patients with respiratory tract infections in Thailand.
abstract: A total of 400 clinical Streptococcus pneumoniae strains from patients with respiratory diseases were collected from January 2002 to December 2005. In this study, an increased prevalence of penicillin-nonsusceptible S. pneumoniae (PNSP) from 63% in 2002-2003 to 69% in 2004-2005 was found. During 2004-2005, 56% were erythromycin-nonsusceptible S. pneumoniae (ENSP) and 54% were both PNSP and ENSP. The PNSP, ENSP and PNSP+ENSP groups showed similar trends, ie, sensitive to amoxicillin/clavulanate (range 97.2-98.5%), levofloxacin (range 90.7-92.4%), ceftriaxone (range 87.1-89.4%), and ofloxacin (range 64.8-66.1%). Lower levels of susceptibility were detected for azithromycin, clarithromycin, cefdinir, cefprozil, clindamycin, co-trimoxazole, chloramphenicol and tetracycline in penicillin and erythromycin-nonsusceptible strains. Of the macrolide-resistant S. pneumoniae, 55% of strains exhibited the M phenotype and 45% the constitutive MLS(B) phenotype. No pneumococci with the inducible MLS(B) phenotype were detected in Thailand.

title: Risk factors and clinical outcomes of penicillin resistant S. pneumoniae community-acquired pneumonia in Khon Kaen, Thailand.
abstract: To determine the prevalence, risk factors and clinical outcomes of penicillin-resistant S. pneumoniae (PRSP) in community-acquired pneumonia (CAP), a cross-sectional study was conducted between January 1995 and December 2004 at Srinagarind Hospital, Khon Kaen, Thailand. Patients hospitalized with CAP and culture proved to be S. pneumoniae were included. PRSP was found in 22 of 64 (34.4%) patients. The MIC levels of penicillin non-susceptible strains ranged between 0.25 and 0.75 microg/ml. Resistance to other antibiotics ranked: cotrimoxazole (51.6%), tetracycline (26.6%), erythromycin (20.6%), lincomycin (18.7%), chloramphenicol (12.5%) and ampicillin (1.6%). None of the isolates was resistant to cephalothin. The significant risk factors for PRSP infection were previous antibiotic use within 3 months (Adjusted OR 40.83, 95% CI 3.71 to 449.41) and alcoholism (Adjusted OR 8.82, 95% 1.25 to 62.46). Bacteremia and empyema thoracis were found more commonly in PRSP than PSSP infection, but not statistically significant. Pneumonia-related mortality was nearly the same, PRSP 9.1% vs PSSP 9.5% (p = 0.96). The reason why the clinical outcomes of these two groups were not different may be the patients were infected with mildly resistant organisms. Thus, pneumonia caused by intermediate-level penicillin resistant S. pneumoniae appears to be adequately treated with beta-lactams or aminopenicillin antibiotics. The MIC levels of penicillin resistance should be monitored further. The need for antibiotics active against drug-resistant S. pneumoniae was required if high-level penicillin resistance was detected.

title: Pulmonary melioidosis in Cambodia: A prospective study
abstract: Melioidosis is a disease caused by Burkholderia pseudomallei and considered endemic in South-East Asia but remains poorly documented in Cambodia. We report the first series of hospitalized pulmonary melioidosis cases identified in Cambodia describing clinical characteristics and outcomes.  We characterized cases of acute lower respiratory infections (ALRI) that were identified through surveillance in two provincial hospitals. Severity was defined by systolic blood pressure, cardiac frequency, respiratory rate, oxygen saturation and body temperature. B. pseudomallei was detected in sputum or blood cultures and confirmed by API20NE gallery. We followed up these cases between 6 months and 2 years after hospital discharge to assess the cost-of-illness and long-term outcome.  During April 2007 - January 2010, 39 ALRI cases had melioidosis, of which three aged ≤2 years; the median age was 46 years and 56.4% were males. A close contact with soil and water was identified in 30 patients (76.9%). Pneumonia was the main radiological feature (82.3%). Eleven patients were severe cases. Twenty-four (61.5%) patients died including 13 who died within 61 days after discharge. Of the deceased, 23 did not receive any antibiotics effective against B. pseudomallei. Effective drugs that were available did not include ceftazidime. Mean total illness-related costs was of US$65 (range $25-$5000). Almost two-thirds (61.5%) incurred debt and 28.2% sold land or other belongings to pay illness-related costs.  The observed high fatality rate is likely explained by the lack or limited access to efficient antibiotics and under-recognition of the disease among clinicians, which led to inappropriate therapy.

title: Clinical manifestation of pulmonary melioidosis in adults.
abstract: Between 1996 and 2002, 162 cases of pulmonary melioidosis were reported from Srinagarind Hospital, Khon Kaen, northeast Thailand, 90 acute vs 72 subacute/chronic. Patients averaged 50 years of age and half worked as farmers. The male to female ratio was between 2 and 3 to 1 depending on the subgrouping. Burkholderia pseudomallei was confirmed by a culture or a four-fold rise in titer in the majority of cases, while the others were presumptive diagnoses based on response to treatment. Pulmonary melioidosis presented as either acute fulminant pneumonia or as an indolent disease. The common concurrent medical illness was diabetes mellitus. Mean incubation of the acute vs the sub-acute/chronic form was 8.7 vs 54.4 days, respectively. Leukocytosis was detected in 70% of cases. Sputum Gram's stain was not sensitive for diagnosis. Sputum culture and blood culture were diagnostic for 31.1 vs 22.2 and 40 vs 37.5% of the acute vs subacute/chronic forms, respectively. The common radiographic patterns for acute pneumonia were localized patchy alveolar infiltrate or hematogenous pattern. A bilateral diffuse patchy alveolar infiltration or multiple nodular lesions characterized the latter. Upper-lobe involvement with early cavitation and rapid progression were common. In the subacute/chronic forms, the radiographic pattern sometimes mimicked tuberculosis, with upper lobe involvement, patchy alveolar infiltrate with cavities or fibroreticular lesions. In approximately 30% of cases, liver and/or splenic abscess were common sites of extrapulmonary infection. Respiratory failure and septic shock from acute pulmonary melioidosis was 20% fatal. Early empirical antibiotic therapy should be given for severe pneumonia.

title: Acute lower respiratory infections in ≥5 year -old hospitalized patients in Cambodia, a low-income tropical country: clinical characteristics and pathogenic etiology
abstract: BackgroundFew data exist on viral and bacterial etiology of acute lower respiratory infections (ALRI) in ≥5 year –old persons in the tropics.MethodsWe conducted active surveillance of community-acquired ALRI in two hospitals in Cambodia, a low-income tropical country. Patients were tested for acid-fast bacilli (AFB) by direct sputum examination, other bacteria by blood and/or sputum cultures, and respiratory viruses using molecular techniques on nasopharyngeal/throat swabs. Pulmonologists reviewed clinical/laboratory data and interpreted chest X-rays (CXR) to confirm ALRI.ResultsBetween April 2007 - December 2009, 1,904 patients aged ≥5 years were admitted with acute pneumonia (50.4%), lung sequelae-associated ALRI (24.3%), isolated pleural effusions (8.9%) or normal CXR-related ALRI (17.1%); 61 (3.2%) died during hospitalization. The two former diagnoses were predominantly due to bacterial etiologies while viral detection was more frequent in the two latter diagnoses. AFB-positive accounted for 25.6% of acute pneumonia. Of the positive cultures (16.8%), abscess-prone Gram-negative bacteria (39.6%) and Haemophilus influenzae (38.0%) were most frequent, followed by Streptococcus pneumoniae (17.7%). Of the identified viruses, the three most common viruses included rhinoviruses (49.5%), respiratory syncytial virus (17.7%) and influenza viruses (12.1%) regardless of the diagnostic groups. Wheezing was associated with viral identification (31.9% vs. 13.8%, p < 0.001) independent of age and time-to-admission.ConclusionsHigh frequency of H. influenzae and S. pneumoniae infections support the need for introduction of the respective vaccines in the national immunization program. Tuberculosis was frequent in patients with acute pneumonia, requiring further investigation. The relationship between respiratory viruses and wheezing merits further studies.

title: Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines
abstract: Since the last British study of the microbial aetiology of community acquired pneumonia (CAP) about 20 years ago, new organisms have been identified (for example, Chlamydia pneumoniae), new antibiotics introduced, and fresh advances made in microbiological techniques. Pathogens implicated in CAP in adults admitted to hospital in the UK using modern and traditional microbiological investigations are described.  Adults aged 16 years and over admitted to a teaching hospital with CAP over a 12 month period from 4 October 1998 were prospectively studied. Samples of blood, sputum, and urine were collected for microbiological testing by standard culture techniques and new serological and urine antigen detection methods.  Of 309 patients admitted with CAP, 267 fulfilled the study criteria; 135 (50.6%) were men and the mean (SD) age was 65.4 (19.6) years. Aetiological agents were identified from 199 (75%) patients (one pathogen in 124 (46%), two in 53 (20%), and three or more in 22 (8%)): Streptococcus pneumoniae 129 (48%), influenza A virus 50 (19%), Chlamydia pneumoniae 35 (13%), Haemophilus influenzae 20 (7%), Mycoplasma pneumoniae 9 (3%), Legionella pneumophilia 9 (3%), other Chlamydiaspp 7 (2%), Moraxella catarrhalis 5 (2%), Coxiella burnetii 2 (0.7%), others 8 (3%). Atypical pathogens were less common in patients aged 75 years and over than in younger patients (16% v27%; OR 0.5, 95% CI 0.3 to 0.9). The 30 day mortality was 14.9%. Mortality risk could be stratified by the presence of four “core” adverse features. Three of 60 patients (5%) infected with an atypical pathogen died.  S pneumoniae remains the most important pathogen to cover by initial antibiotic therapy in adults of all ages admitted to hospital with CAP. Atypical pathogens are more common in younger patients. They should also be covered in all patients with severe pneumonia and younger patients with non-severe infection.

title: Burden of disease caused by Haemophilus influenzae type b in children younger than 5 years: global estimates
abstract: Haemophilus influenzae type b (Hib) is a leading cause of childhood bacterial meningitis, pneumonia, and other serious infections. Hib disease can be almost completely eliminated through routine vaccination. We assessed the global burden of disease to help national policy makers and international donors set priorities.



We did a comprehensive literature search of studies of Hib disease incidence, case-fatality ratios, age distribution, syndrome distribution, and effect of Hib vaccine. We used vaccine trial data to estimate the proportion of pneumonia cases and pneumonia deaths caused by Hib. We applied these proportions to WHO country-specific estimates of pneumonia cases and deaths to estimate Hib pneumonia burden. We used data from surveillance studies to develop estimates of incidence and mortality of Hib meningitis and serious non-pneumonia, non-meningitis disease. If available, high-quality data were used for national estimates of Hib meningitis and non-pneumonia, non-meningitis disease burden. Otherwise, estimates were based on data from other countries matched as closely as possible for geographic region and child mortality. Estimates were adjusted for HIV prevalence and access to care. Disease burden was estimated for the year 2000 in children younger than 5 years.



We calculated that Hib caused about 8.13 million serious illnesses worldwide in 2000 (uncertainty range 7.33-13.2 million). We estimated that Hib caused 371,000 deaths (247,000-527,000) in children aged 1-59 months, of which 8100 (5600-10,000) were in HIV-positive and 363,000 (242,000-517,000) in HIV-negative children.



Global burden of Hib disease is substantial and almost entirely vaccine preventable. Expanded use of Hib vaccine could reduce childhood pneumonia and meningitis, and decrease child mortality.



GAVI Alliance and the Vaccine Fund.

title: Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates
abstract: Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and sepsis in children worldwide. However, many countries lack national estimates of disease burden. Effective interventions are available, including pneumococcal conjugate vaccine and case management. To support local and global policy decisions on pneumococcal disease prevention and treatment, we estimated country-specific incidence of serious cases and deaths in children younger than 5 years.



We measured the burden of pneumococcal pneumonia by applying the proportion of pneumonia cases caused by S pneumoniae derived from efficacy estimates from vaccine trials to WHO country-specific estimates of all-cause pneumonia cases and deaths. We also estimated burden of meningitis and non-pneumonia, non-meningitis invasive disease using disease incidence and case-fatality data from a systematic literature review. When high-quality data were available from a country, these were used for national estimates. Otherwise, estimates were based on data from neighbouring countries with similar child mortality. Estimates were adjusted for HIV prevalence and access to care and, when applicable, use of vaccine against Haemophilus influenzae type b.



In 2000, about 14.5 million episodes of serious pneumococcal disease (uncertainty range 11.1-18.0 million) were estimated to occur. Pneumococcal disease caused about 826,000 deaths (582,000-926,000) in children aged 1-59 months, of which 91,000 (63,000-102,000) were in HIV-positive and 735,000 (519,000-825,000) in HIV-negative children. Of the deaths in HIV-negative children, over 61% (449,000 [316,000-501,000]) occurred in ten African and Asian countries.



S pneumoniae causes around 11% (8-12%) of all deaths in children aged 1-59 months (excluding pneumococcal deaths in HIV-positive children). Achievement of the UN Millennium Development Goal 4 for child mortality reduction can be accelerated by prevention and treatment of pneumococcal disease, especially in regions of the world with the greatest burden.



GAVI Alliance and the Vaccine Fund.

title: Clinical features and epidemiology of melioidosis pneumonia: results from a 21-year study and review of the literature.
abstract: Melioidosis is an important cause of community-acquired sepsis in Southeast Asia and northern Australia, and pneumonia is the most common presentation. Clinical manifestations range from acute fulminant sepsis to chronic infection mimicking tuberculosis. Pneumonia may be the primary presenting feature, or it can develop secondary to initial disease at a distant focus.



A prospective database of all melioidosis patients at Royal Darwin Hospital (Australia) between 1989 and 2010 was reviewed.



Of 624 patients with culture-confirmed melioidosis, 319 (51%) presented with pneumonia as the primary diagnosis. Acute/subacute presentations accounted for the majority of primary pneumonia cases (91%); chronic disease was seen less commonly (9%). Secondary pneumonia developed in 20% of patients with other primary melioidosis presentations and was particularly common in those with positive blood cultures. Risk factors for presentation with primary pneumonia (compared with other primary presentations) were rheumatic heart disease or congestive cardiac failure, chronic obstructive pulmonary disease, smoking, and diabetes mellitus, with P < .05 for these conditions in a multivariate logistic regression model. Patients presenting with pneumonia more frequently developed septic shock (33% vs 10%; P < .001) and died (20% vs 8%; P <.001) compared with patients with other primary presentations. Multilobar disease occurred in 28% of primary pneumonia patients and was associated with greater mortality (32%) than in those with single-lobe disease (14%; P < .001).



Melioidosis pneumonia is often a rapidly progressive illness with high mortality, particularly among those with multilobar disease. Risk factors have been identified, and early diagnosis and treatment should be priorities.

title: A first report of pulmonary melioidosis in Cambodia.
abstract: Melioidosis has never been officially reported from Cambodia. Here we report two cases, a 58-year-old male (case 1) and a 49-year-old female (case 2) who presented with respiratory illnesses featuring multiple lung abscesses. The sputum culture of both patients, taken in the framework of a laboratory-based study on aetiologies of (sub-)acute respiratory infections among hospitalized patients in southern Cambodia, grew Burkholderia pseudomallei. The most striking aspect of these case stories was the extent of the delays in diagnosis. Presenting with a 1-month history of respiratory symptoms, case 1 was first suspected of tuberculosis (TB) infection, and then misdiagnosed as 'metastatic lung cancer' in Phnom Penh, Cambodia. Case 2 suffered from pulmonary infections for >10 years, during which time she was treated for TB four times. Neither patient ever produced acid-fast-bacilli (AFB)-positive sputum. Following our laboratory confirmation, the patients were traced for re-admission. Under the 'classical' trimethoprim sulphamethoxazole, chloramphenicol and doxycycline treatment, their clinical status improved considerably within 2 weeks. The two study cases illustrate issues relating to the misdiagnosis of melioidosis in Cambodia; an unfamiliarity of clinicians with the disease, which is associated with a high prevalence of TB. Therefore, a heightened awareness of melioidosis among clinicians would have a substantial impact on public health as the non-septicaemic form of the disease is potentially treatable with antibiotics that are available in Cambodian public hospitals.

title: High Prevalence of Antimicrobial Resistance among Clinical Streptococcus pneumoniae Isolates in Asia (an ANSORP Study)
abstract: A total of 685 clinical Streptococcus pneumoniae isolates from patients with pneumococcal diseases were collected from 14 centers in 11 Asian countries from January 2000 to June 2001. The in vitro susceptibilities of the isolates to 14 antimicrobial agents were determined by the broth microdilution test. Among the isolates tested, 483 (52.4%) were not susceptible to penicillin, 23% were intermediate, and 29.4% were penicillin resistant (MICs ≥ 2 mg/liter). Isolates from Vietnam showed the highest prevalence of penicillin resistance (71.4%), followed by those from Korea (54.8%), Hong Kong (43.2%), and Taiwan (38.6%). The penicillin MICs at which 90% of isolates are inhibited (MIC90s) were 4 mg/liter among isolates from Vietnam, Hong Kong, Korea, and Taiwan. The prevalence of erythromycin resistance was also very high in Vietnam (92.1%), Taiwan (86%), Korea (80.6%), Hong Kong (76.8%), and China (73.9%). The MIC90s of erythromycin were >32 mg/liter among isolates from Korea, Vietnam, China, Taiwan, Singapore, Malaysia, and Hong Kong. Isolates from Hong Kong showed the highest rate of ciprofloxacin resistance (11.8%), followed by isolates from Sri Lanka (9.5%), the Philippines (9.1%), and Korea (6.5%). Multilocus sequence typing showed that the spread of the Taiwan19F clone and the Spain23F clone could be one of the major reasons for the rapid increases in antimicrobial resistance among S. pneumoniae isolates in Asia. Data from the multinational surveillance study clearly documented distinctive increases in the prevalence rates and the levels of antimicrobial resistance among S. pneumoniae isolates in many Asian countries, which are among the highest in the world published to date.

title: The emerging NDM carbapenemases.
abstract: Carbapenems were the last β-lactams retaining near-universal anti-Gram-negative activity, but carbapenemases are spreading, conferring resistance. New Delhi metallo-β-lactamase (NDM) enzymes are the latest carbapenemases to be recognized and since 2008 have been reported worldwide, mostly in bacteria from patients epidemiologically linked to the Indian subcontinent, where they occur widely in hospital and community infections, and also in contaminated urban water. The main type is NDM-1, but minor variants occur. NDM enzymes are present largely in Enterobacteriaceae, but also in non-fermenters and Vibrionaceae. Dissemination predominantly involves transfer of the blaNDM-1 gene among promiscuous plasmids and clonal outbreaks. Bacteria with NDM-1 are typically resistant to nearly all antibiotics, and reliable detection and surveillance are crucial.

title: Update of contemporary antimicrobial resistance rates across China: reference testing results for 12 medical centers (2011).
abstract: Antimicrobial resistance (R) surveillance across Asia and especially in China has documented unique patterns and mechanisms. This 2011 study reports results for 2278 isolates from 12 hospitals in China (94-216 strains/site); most from bacteremia (20.4%), pneumonias (29.1%), or skin and skin structure infections (20.9%). Samples were tested by reference broth microdilution methods, interpreted by published susceptibility (S) breakpoints. The most common species were Staphylococcus aureus (343, 45.8% MRSA), Escherichia coli (EC; 288), Pseudomonas aeruginosa (PSA; 221), Klebsiella spp. (KSP; 208), acinetobacters (ACB; 178), enterobacters (155), Streptococcus pneumoniae (SPN; 154, 46.8% penicillin-S), and enterococci (ENT; 137). Among 849 Gram-positive (GP) cocci, linezolid, tigecycline (TIG), daptomycin, and vancomycin provided best antimicrobial coverage (≥99.7% S). Resistance patterns of concern were 0.3% VISA, 15.4% teicoplanin non-S coagulase-negative staphylococci, 1.5% vancomycin-R ENT (all Enterococcus faecium), 1.9% levofloxacin-R β-haemolytic streptococci, and 35.1 and 12.7% ceftriaxone-non-S rates for SPN and viridans group streptococci, respectively. For Gram-negative bacilli, R among Enterobacteriaceae was highest against β-lactams (extended spectrum β-lactamase-phenotype strains at 73.6 and 42.8% in EC and KSP, respectively; carbapenem-R was only 2.1-4.3% with KPC and IMP type enzymes detected in KSP). The widest spectrum agents were cefoperazone/sulbactam (79.5-86.1%), piperacillin/tazobactam (88.9-92.0%), TIG (98.6-100%), amikacin (AMK; 91.8-93.7%), and meropenem (95.7-97.1% S). PSA was most inhibited by AMK (90.5% S) and colistin (COL; 99.5%), with cefepime (67.9%) best among the tested β-lactams. Only COL (100% S) and TIG (MIC90, 2 μg/mL) showed significant potencies against ACB. In conclusion, R among pathogens from 12 Chinese hospitals illustrates several agents active against GP pathogens, but more serious R problems were noted among Enterobacteriaceae, PSA, and ACB. Combination treatment for the latter multidrug-R strains appears necessary, guided by local antibiograms and national surveillance results applying reference methods.

title: OXA-181-producing Klebsiella pneumoniae establishing in Singapore
abstract: BackgroundCarbapenemase producing Enterobacteriaceae are becoming a major public health concern globally, however, relatively little is known about the molecular and clinical epidemiology of these organisms in many parts of the world.MethodsAs part of a laboratory surveillance programme, 96 carbapenem non-susceptible Enterobacteriaceae isolates from clinical samples from patients in seven hospitals were referred for investigation for carbapenemases. Using polymerase chain reaction (PCR) to screen for a collection of genes encoding carbapenemases, 33 of 96 (34.5%) isolates were confirmed as carbapenemase producers. NDM-1 producers were the most prevalent at 64% (21/33) whilst OXA-181 was the second most common carbapenemase constituting 24.5% (8/33) of the carbapenemase producing isolates. Seven of these eight OXA-181 positive isolates underwent further characterisation with screening for other transmissible antimicrobial resistance determinants using PCR. Clonal relatedness was explored using Multilocus sequence typing (MLST) and Pulsed Field Gel Electrophoresis (PFGE). Plasmid characterisation was performed including restriction analysis and transfer by conjugation or transformation.ResultsIn addition to the OXA-181 gene, all contained other transmissible resistance determinants including extended spectrum β-lactamases, oxacillinases or 16S rRNA methylase genes, but none contained metallo-β-lactamases or serine carbapenemases. All isolates had a multidrug resistant phenotype with two isolates being resistant to every antibiotic tested including colistin. Multilocus sequence typing confirmed five isolates belonged to ST17 and two to ST14, with those belonging to the same sequence type having identical PFGE profiles. The OXA-181 gene was typically carried on large plasmids which were mostly non-conjugative.ConclusionsOXA-181 carbapenemase appears to be an important and probably under-recognised cause of carbapenem resistance in Enterobacteriaceae in Singapore. Further coordinated research into clinical and molecular epidemiology of carbapenemases is urgently required in Singapore and throughout Asia.

title: Arrival of Klebsiella pneumoniae carbapenemase (KPC)-2 in Taiwan.
abstract: Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

title: Characteristics of carbapenem-resistant Enterobacteriaceae isolates from Korea.
abstract: In this study, the characteristics of carbapenem-resistant Enterobacteriaceae (CRE) isolates from Korea was investigated. A total of 22 CRE isolates were investigated, and most were identified as Klebsiella pneumoniae (16 isolates). In vitro antimicrobial susceptibility testing, multilocus sequence typing, and pulsed-field gel electrophoresis were performed. Extended-spectrum β-lactamase (ESBL) and carbapenemase genes were detected using gene amplification and sequencing. Efflux pump activity and inactivating mutations in OmpK35/36 were also investigated. Among 22 CRE isolates, only 5 produced metallo-β-lactamases (3 NDM-1, one VIM-2 and one IMP-1). Four and 2 K. pneumoniae and Serratia marcescens isolates showed resistance to polymyxins, respectively, and 2 CRE isolates (1 K. pneumoniae and C. freundii) were resistant to tigecycline. The prevalent carbapenem resistance mechanism found in K. pneumoniae might be porin defects. The most prevalent clone of carbapenem-resistant K. pneumoniae was ST11 (56.3%), which is the most frequently identified clone among ESBL-producing K. pneumoniae isolates from Korea. Three NDM-1-producing K. pneumoniae isolates belonged to a single clone (ST340) despite their different antimicrobial susceptibilities. In the present study, the clonal dissemination of carbapenem-resistant K. pneumoniae isolates (ST11) and NDM-1-producing K. pneumoniae isolates (ST340) was determined. Polymyxin- and tigecycline-resistant CRE isolates were also identified, which limits treatment options for infections causes by these organisms.

title: Emergence of NDM-1- and IMP-14a-producing Enterobacteriaceae in Thailand.
abstract: To detect carbapenemases in clinical isolates of Enterobacteriaceae collected from patients in a university hospital in Thailand between October 2010 and August 2011.



A total of 4818 Enterobacteriaceae isolates were screened for the presence of carbapenemases by ertapenem and imipenem disc diffusion tests. All positive screening isolates were subjected to modified Hodge test, phenylboronic acid- and EDTA-carbapenem combined disc tests and two multiplex PCRs of bla(IMP), bla(VIM), bla(SPM), bla(SIM) and bla(GIM), and of bla(KPC), bla(NDM) and bla(OXA-48). Carbapenemase-producing isolates were typed by PFGE and then characterized by antimicrobial susceptibility tests. Conjugation was performed using a broth culture mating method.



Two isolates each of Escherichia coli, Klebsiella pneumoniae and Citrobacter freundii produced NDM-1, whereas two other isolates of K. pneumoniae produced IMP-14a. DNA fingerprints revealed that the metallo-β-lactamase (MBL)-producing isolates were of different strains except for clonal strains of C. freundii. In vitro transfer of carbapenem resistance was successful for the eight MBL-producing isolates. All MBL producers were susceptible to colistin and tigecycline. The six NDM-producing isolates were recovered from the urine of three patients, who had no history of travel outside Thailand. Interestingly, one patient had chronic urinary tract infections caused by a K. pneumoniae strain and two strains of E. coli producing NDM-1.



Surveillance of carbapenemases, particularly NDM-1, in Enterobacteriaceae is urgently needed to control and prevent the spread of these resistance determinants in our country.

title: High burden of antimicrobial resistance in Asia.
abstract: Antimicrobial resistance is associated with high mortality rates and high medical costs. Marked variations in the resistance profiles of bacterial and fungal pathogens as well as the quality of public hygiene have had a considerable impact on the effectiveness of antimicrobial agents in Asian countries. In Asia, one of the epicentres of antimicrobial drug resistance, there is an alarming number of antibiotic-resistant species, including penicillin- and erythromycin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, multidrug-resistant (MDR) Acinetobacter baumannii, extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae (particularly mediated by CTX-M-9, CTX-M-14 and CTX-M-15), New Delhi metallo-β-lactamase 1 (NDM-1)-producing Enterobacteriaceae, MDR Salmonella enterica serotypes Choleraesuis and Typhi, carbapenem-resistant A. baumannii (OXA-58 and OXA-23 carbapenemases) and azole-resistant Candida glabrata. A few clones of MDR A. baumannii and hospital-acquired meticillin-resistant Staphylococcus aureus (MRSA) have been widely disseminated in hospital settings in Asia, and K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains have been widely distributed in China. In addition, the emergence of extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) has illustrated the need for regular monitoring of resistance profiles of clinical isolates as well as the deliberative use of fluoroquinolones. Continuous surveillance of resistance data from clinical isolates as well as implementation of strict infection control policies in healthcare settings are required to mitigate the progression of antimicrobial resistance.

title: Antimicrobial Resistance in Asia: Current Epidemiology and Clinical Implications
abstract: Antimicrobial resistance has become one of the most serious public health concerns worldwide. Although circumstances may vary by region or country, it is clear that some Asian countries are epicenters of resistance, having seen rapid increases in the prevalence of antimicrobial resistance of major bacterial pathogens. In these locations, however, the public health infrastructure to combat this problem is very poor. The prevalence rates of methicillin-resistant Staphylococcus aureus (MRSA), macrolide-resistant Streptococcus pneumoniae, and multidrug-resistant enteric pathogens are very high due to the recent emergence of extremely drug-resistant gram-negative bacilli in Asia. Because antimicrobial options for these pathogens are extremely limited, infections caused by antimicrobial-resistant bacteria are often associated with inappropriate antimicrobial therapy and poor clinical outcomes. Physicians should be aware of the current epidemiological status of resistance and understand the appropriate use of antimicrobial agents in clinical practice. This review focuses on describing the epidemiology and clinical implications of antimicrobial-resistant bacterial infections in Asian countries.

title: Fluoroquinolones are associated with delayed treatment and resistance in tuberculosis: a systematic review and meta-analysis.
abstract: Current guidelines for treating community-acquired pneumonia recommend the use of fluoroquinolones for high-risk patients. Previous studies have reported controversial results as to whether fluoroquinolones are associated with delayed diagnosis and treatment of pulmonary tuberculosis (TB) and the development of fluoroquinolone-resistant Mycobacterium tuberculosis. We performed a systematic review and meta-analysis to clarify these issues.



The following databases were searched through September 30, 2010: PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science, BIOSIS Previews, and the ACP Journal Club. We considered studies that addressed the issues of delay in diagnosis and treatment of TB and the development of resistance.



Nine eligible studies (four for delays and five for resistance issues) were included in the meta-analysis from the 770 articles originally identified in the database search. The mean duration of delayed diagnosis and treatment of pulmonary TB in the fluoroquinolone prescription group was 19.03 days, significantly longer than that in the non-fluoroquinolone group (95% confidence interval (CI) 10.87 to 27.18, p<0.001). The pooled odds ratio of developing a fluoroquinolone-resistant M. tuberculosis strain was 2.70 (95% CI 1.30 to 5.60, p=0.008). No significant heterogeneity was found among studies in the meta-analysis.



Empirical fluoroquinolone prescriptions for pneumonia are associated with longer delays in diagnosis and treatment of pulmonary TB and a higher risk of developing fluoroquinolone-resistant M. tuberculosis.

title: Fluoroquinolone susceptibility in Mycobacterium tuberculosis after pre-diagnosis exposure to older- versus newer-generation fluoroquinolones.
abstract: Fluoroquinolone exposure before tuberculosis (TB) diagnosis is common. We anticipated that exposure to older-generation fluoroquinolones is associated with greater fluoroquinolone MICs in Mycobacterium tuberculosis than exposure to newer agents. A nested case-control study was performed among newly diagnosed TB patients reported to the Tennessee Department of Health (January 2002-December 2009). Each fluoroquinolone-resistant case (n=25) was matched to two fluoroquinolone-susceptible controls (n=50). Ciprofloxacin and ofloxacin were classified as older-generation fluoroquinolones; levofloxacin, moxifloxacin and gatifloxacin were considered newer agents. There was no difference between median ofloxacin MIC for isolates from 9 patients exposed only to older fluoroquinolones, 25 exposed only to newer fluoroquinolones, 6 exposed to both and 35 fluoroquinolone-unexposed patients (Kruskal-Wallis, P=0.35). Using multivariate proportional odds logistic regression adjusting for age and sex, duration of exposure to newer fluoroquinolones was independently associated with higher MIC (OR=1.79, 95% CI 1.22-2.64), but duration of exposure to older fluoroquinolones was not (OR=0.94, 95% CI 0.50-1.78). Isolates from patients exposed only to newer fluoroquinolones tended to have mutations at gyrA codons 90, 91 or 94 more frequently than those exposed only to older fluoroquinolones (44% vs. 11%). We were surprised to find that duration of exposure to newer fluoroquinolones, but not older ones, was independently associated with higher ofloxacin MIC. This suggests that the mutant selection window lower boundary is likely to have clinical relevance; caution is warranted when newer fluoroquinolones are prescribed to patients with TB risk factors.

title: Describing the epidemiology and aetiology of bacterial pneumonia in children: an unresolved problem.
abstract: Acute lower respiratory infections are among the most common problems in children worldwide. In developing countries, they constitute the most common cause of mortality in children aged less than five years, leading to an estimated 1.9 million deaths annually, most of which are thought to be due to pneumonia (1). Despite the frequency and severity of this condition, the burden and epidemiology of disease have been difficult to describe with sufficient accuracy because of the lack of an adequate definition of pneumonia for epidemiological purposes and of the lack of sensitive and specific tests to establish bacterial aetiology. Some of these problems, which still remain unresolved, are evident in the study reported by Nacul et al. in this issue of the Journal (2). Defining pneumonia Conventionally, pneumonia is clinically diagnosed based on a combination of clinical signs and symptoms and confirmed by findings of chest radiography. Simple clinical signs, such as tachypnoea and lower chest in-drawing, have been shown to be reliable signs of pneumonia (3). While these signs are appropriate for case management in primary healthcare programmes where high sensitivity is important, they are not sufficiently specific to accurately estimate the burden of disease and give low efficacy estimates for interventions that are aimed specifically at preventing bacterial pneumonia. Auscultatory findings, such as crepitations and bronchial breath sounds, have been conventionally used by physicians in the clinical diagnosis of pneumonia. However, these findings are subjective and highly dependent on the skill of the observer. As a result, the diagnosis of pneumonia using auscultatory findings has been difficult to standardize, and inter-observer agreement regarding the presence and absence of these signs has been poor (4). Radiography is considered to be the gold standard for the diagnosis of pneumonia. However, different studies have varied in the radiological findings used to define pneumonia. While some studies have classified only cases with alveolar consolidation as pneumonia, others have considered the presence of any pulmonary parenchymal infiltrates as constituting pneumonia. Furthermore, there is relatively poor agreement even between radiologists on the presence or absence of infiltrates in paediatric chest radiographs. This variability persists even when standard definitions and reporting forms are used. Analysis of the readings of four trained paediatric radiologists who read chest radiographs from two different studies using common definitions and reporting forms showed that while there was reasonable agreement for alveolar consolidation, agreement was low for many other findings (Weber M. Personal communication, 2004). Despite these limitations, radiography still remains the best available tool to diagnose pneumonia. Since bacterial pneumonia is thought to account for the majority of pneumonia-related deaths and since current interventions, such as vaccines and case management, focus on bacterial disease, the World Health Organization (WHO) initiated a process to improve the interobserver agreement for categorizing pneumonia with alveolar consolidation, the finding that is most representative of this condition. Asimplified definition, coupled with a training programme, and the system of two independent readings with an arbitration reading of those images where the two primary readings were discordant, was developed and tested (5). The use of the definitions and methods resulted in reasonably good agreement in categorizing pneumonia with alveolar consolidation and has been used in Haemophilus influenzae type b (Hib) and pneumococcal vaccine trials to determine the effect of these vaccines on pneumonia (6). The same definitions are also currently being used for documenting the burden of pneumonia in several studies in developing countries. Available data suggest that, while the radiological definitions of WHO are enriched for the diagnosis of bacterial pneumonia, they are still not optimally sensitive and specific (7-12). …

title: Validation of immunoglobulin G enzyme-linked immunosorbent assay for antibodies to pneumococcal surface adhesin A in the diagnosis of pneumococcal pneumonia among adults in Kenya.
abstract: Epidemiologic studies of pneumococcal pneumonia, including vaccine efficacy trials, are hampered by a lack of sensitive and specific diagnostic tests. Pneumococcal surface adhesin A (PsaA) is a genetically conserved, surface-expressed protein common to all serotypes of Streptococcus pneumoniae and is highly immunogenic. Detection of anti-PsaA immunoglobulin G by recombinant PsaA enzyme-linked immunosorbent assay was evaluated for diagnosis of pneumococcal pneumonia in paired serum samples from 4 adult populations: 47 healthy control subjects, 56 clinic control subjects without pneumococcal disease syndromes, 109 patients with pneumococcal pneumonia, and 93 pneumonia patients with no evidence of pneumococcal etiology. By considering a 2-fold increase in antibody concentration as positive, sensitivity was 0.70, and specificity was 0.98. With a 1.3-fold increase, these were 0.89 and 0.98, respectively. The test's performance was not affected by the patients' human immunodeficiency virus status or by the pneumococcal serotype. The combination of high sensitivity and high specificity makes this an ideal assay for epidemiologic studies of pneumococcal pneumonia.

title: Evaluation of Binax now Streptococcus pneumoniae urinary antigen test in children in a community with a high carriage rate of pneumococcus.
abstract: Pneumococcal antigen was present in urine from 49 of 102 well Gambian children. Eighty-nine of the 102 were nasopharyngeal carriers of pneumococci. The positive predictive value for carriage was 96%, and the negative predictive value was 22%. The test is not useful for predicting etiology of disease in populations with a high rate of nasopharyngeal carriage of pneumococci.

title: Gaps in policy-relevant information on burden of disease in children: a systematic review
abstract: Valid information about cause-specific child mortality and morbidity is an essential foundation for national and international health policy. We undertook a systematic review to investigate the geographical dispersion of and time trends in publication for policy-relevant information about children's health and to assess associations between the availability of reliable data and poverty.



We identified data available on Jan 1, 2001, and published since 1980, for the major causes of morbidity and mortality in young children. Studies with relevant data were assessed against a set of inclusion criteria to identify those likely to provide unbiased estimates of the burden of childhood disease in the community.



Only 308 information units from more than 17,000 papers identified were regarded as possible unbiased sources for estimates of childhood disease burden. The geographical distribution of these information units revealed a pattern of small well-researched populations surrounded by large areas with little available information. No reliable population-based data were identified from many of the world's poorest countries, which account for about a third of all deaths of children worldwide. The number of new studies diminished over the last 10 years investigated.



The number of population-based studies yielding estimates of burden of childhood disease from less developed countries was low. The decreasing trend over time suggests reductions in research investment in this sphere. Data are especially sparse from the world's least developed countries with the highest child mortality. Guidelines are needed for the conduct of burden-of-disease studies together with an international research policy that gives increased emphasis to global equity and coverage so that knowledge can be generated from all regions of the world.