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Empiric use of antibiotics remains as cornerstone of treating pneumonia in the absence of effective point-of-care diagnostics for differentiating bacterial from viral infection. Many children who have viral pneumonia will continue to receive antibiotics without benefit. Early reliable detection of viral pneumonia, or early exclusion of bacterial pneumonia, could reduce unnecessary antibiotic therapy, thereby mitigating the risk of emerging antibiotic resistance. While we have been unable to identify a single biomarker or clinical feature that could be used to confidently distinguish bacterial from viral pneumonia, our findings suggest there may be utility in more sophisticated algorithms that integrate a number of clinical, microbiological, inflammatory biomarker, or radiological factors to improve pneumonia diagnostics and better targeting therapies.
The pre-publication history for this paper can be accessed here:
The pre-publication history for this paper can be accessed here:
This is a retrospective and observational study in which data from children and adolescents under 18 years of age, visited to one of the 117 Emergency Departments (EDs) in Korea between 1 January 2007 and 31 December 2014 were analyzed. The data were obtained from the National Emergency Department Information System (NEDIS) for children and adolescents under 18 years of age. The patients with diagnosis codes for CAP, based on International Classification of Disease, 10th revision diagnostic codes (Table 1) which was provided at the time of discharge from ED or after hospitalization were selected to identify eligible cases.
Categorical data was performed chi-square test, depending on age. Annual and seasonal distribution of ED visits were described by the number and % of total. The tau values were calculated using the Mann-Kendall method to analyze increasing or decreasing trends. Monthly incidence rate of diseases from data in 2008–2014 were decomposed and plotted into three components of trend, seasonality and remainder using LOESS procedure. Analyzes were performed using SAS ver. 9.4 (SAS Institute Inc., Cary, NC, USA), with a P value≤0.05 deemed significant.
Institutional Review Boards waived deliberation of this study.
Case management of pneumonia is a strategy by which severity of disease is classified as severe or non-severe. All children receive early, appropriate oral antibiotics, and severe cases are referred for parenteral antibiotics. When implemented in high-burden areas before the availability of conjugate vaccines, case management as part of Integrated Management of Childhood Illness was associated with a 27% decrease in overall child mortality, and 42% decrease in pneumonia-specific mortality. However the predominance of viral causes of pneumonia and low case fatality have prompted concern about overuse of antibiotics. Several randomized controlled trials comparing oral antibiotics to placebo for non-severe pneumonia have been performed [75–77] and others are ongoing. In two studies, performed in Denmark and in India, outcomes of antibiotic and placebo treatments were equivalent [76, 77]. In the third study, in Pakistan, there was a non-significant 24% vs. 20% rate of failure in the placebo group, which was deemed to be non-equivalent to the antibiotic group. Furthermore, because WHO-classified non-severe pneumonia and bronchiolitis might be considered within a spectrum of lower respiratory disease, many children with clinical pneumonia could actually have viral bronchiolitis, for which antibiotics are not beneficial. This has been reflected in British and Spanish national pneumonia guidelines, which do not recommend routine antibiotic treatment for children younger than 2 years with evidence of pneumococcal conjugate vaccination who present with non-severe pneumonia. The United States’ national guidelines recommend withholding antibiotics in children up to age 5 years presenting with non-severe pneumonia. However, given the high mortality from pneumonia in low- and middle-income countries, the lack of easy access to care, and the high prevalence of risk factors for severe disease, revised World Health Organization pneumonia guidelines still recommend antibiotic treatment for all children who meet the WHO pneumonia case definitions.
Use of supplemental oxygen is life-saving, but this is not universally available in low- and middle-income countries; it is estimated that use of supplemental oxygen systems could reduce mortality of children with hypoxic pneumonia by 20%. Identifying systems capacity to increase availability of oxygen in health facilities, and identifying barriers to further implementation are among the top 15 priorities for future childhood pneumonia research. However, up to 81% of pneumonia deaths in 2010 occurred outside health facilities, so there are major challenges with access to health services and health-seeking behavior of vulnerable populations. Identifying and changing the barriers to accessing health care is an important area with the potential to impact the survival and health of the most vulnerable children.
We obtained written informed consent from a parent or a caregiver of the participating children before enrolling them into the study. The study protocol was reviewed and approved by the institutional review boards (IRB; named as Research Review Committee and Ethical Review Committee) of icddr,b. CDC relied on icddr,b’s IRB review.
Before admission, 31 of the 53 patients with viral pneumonia had received antibiotics. Eleven patients showed early treatment failure with a worsened condition. The other 20 patients showed both early and late treatment failure. Two of these 20 patients received effective corticosteroid therapy before admission. The condition of the other 18 patients became worse after antibiotic treatment. The remaining 22 patients had not received antibiotics or corticosteroids before admission, but they were referred to our hospital after their condition worsened. None of these patients had received neuraminidase inhibitors (NIs) before admission.
After admission, 46 of these 53 patients received antibiotics with β-lactams plus macrolides (n=22, 41.5%), fluoroquinolones with or without other antibiotics (n=16, 30.2%), and others (n=8, 15.1%). Antibiotics were not administered to 7 patients after admission because antibiotic treatment administered by their local physicians had failed.
Six of 13 patients with influenza-associated pneumonia received NIs (from the 5th to 23rd day from the onset of initial symptoms). In three of these 6 patients, both NIs and corticosteroids were started simultaneously, and these patients improved. In 4 of the 6 patients, NIs were started without corticosteroids (from the 5th, 8th, and 11th day after the onset of symptoms). NIs were effective in 2 of 3 patients. In the other patient, however, NI was administered from the 11th day after onset, but the patient showed early treatment failure and was switched to corticosteroid therapy from the 14th day, which was effective. In 7 patients who did not receive NIs, 6 received corticosteroid therapy (which was effective) from the 11th, 19th, 22nd, 23rd, 25th, and 47th day, respectively, after the onset of symptoms. The pulmonary shadows of the two other patients who did not receive corticosteroids or NIs improved spontaneously during follow-up. Among the 40 patients suffering from viral pneumonia due to non-influenza viruses, corticosteroids with antibiotics were administered to 21 patients from a median of 15 (range, 6-45) days after the onset of symptoms. Two of these patients died. Corticosteroid therapy was effective in one of these patients; however, this patient experienced repeated episodes of aspiration pneumonia causing their condition to deteriorate until their death. The other patient showed early and late treatment failure with corticosteroid therapy, causing the progressive deterioration of the patient's condition until their death. The other 19 patients received antibiotics without corticosteroids and all survived.
This study highlights the potential benefits of improved diagnostics for respiratory viruses, primarily the potential for decreased antibacterial exposure and thus decreased selective pressure for resistant bacterial isolates. Antibacterial exposure applies selective pressure and promotes colonization/infection by resistant organisms including MRSA and VRE [40, 41]. Halting this process is essential to maintain effective therapeutic options in the future and may be aided by discontinuation of antibacterials in cases of viral pneumonia. In our study, patients with viral pneumonia exposed to long-course antibacterials had more occurrences of subsequent infection or colonization with MDRO isolates. In contrast, the number of patients with subsequent MDRO infection or colonization was not different between groups although this may be due to the small number of patients in each group. No differences in clinical outcomes, including in-hospital mortality and readmission rates, were observed between patient groups. In the setting of viral pneumonia and no coinfecting bacterial pathogens, discontinuation of antibacterials is reasonable in many if not most cases, and may allow for decreased overall antibacterial use. Enhanced diagnostic technologies can potentially be incorporated into antimicrobial stewardship practices to allow for de-escalation of unnecessary antibacterials. These findings warrant further investigation to determine the applicability of an antibacterial de-escalation approach in the setting of viral pneumonia.
Corticosteroids could increase mortality in patients with influenza pneumonia. Randomized controlled studies are needed to further verify this conclusion.
Antibiotics constitute the first-line therapy for bacterial pneumonia. To complement current clinical practice, secondary bacterial pneumonia-infected mice were treated with anti-cANGPTL4 MAb and moxifloxacin, a commonly used antibiotic effective against respiratory infections. The combined treatment significantly prolonged the median survival time of infected mice (80%) compared to zero survival of mice receiving the control IgG treatment or moxifloxacin alone (Fig. 4A; see Fig. S3A in the supplemental material). Moreover, this combined treatment better protected alveolar integrity and reduced residual fluid in the alveolar spaces, thus indicating its efficacy in ameliorating lung edema, diminishing tissue damage, and prolonging survival time (Fig. 4B; Fig. S3B and C). As indicated in Fig. 4B and quantified in Fig. S3C, Flu+S3 superinfection destroyed the alveolar structures and caused severe edema in the lungs of infected wild-type mice. Antibiotic treatment alone protected the alveolar structures but could not clear the edema and infiltration of immune cells. Although the anti-cANGPTL4 or antipneumolysin antibody treatments alone improved lung tissue integrity and reduced edema, these improvements were not as significant as those observed when using a combined treatment with antibiotics and anti-cANGPTL4 MAb or with anti-cANGPTL4 and antipneumolysin antibodies (Fig. 4B; Fig. S3C). The efficacy of a combined approach was further confirmed by marked improvements in the mouse survival rate and lung tissue integrity in treatment groups of wild-type mice receiving antibiotics, anti-cANGPTL4, and antipneumolysin MAb. Similar trends were observed in ANGPTL4−/− mice receiving antibiotic and antipneumolysin treatment (Fig. S3).
Next, we performed transcriptomic analysis of the lung tissues to elucidate the detailed host response factors to secondary pneumococcal pneumonia during the various treatment modalities (Fig. 4C). Compared with antibiotic treatment alone, our analysis indicated that the anti-cANGPTL4 MAb treatment combined with an antibiotic notably improved the immune responses against bacterial infection as well as coagulation function, thus attenuating intra-alveolar hemorrhage and edema in the lungs of secondary bacterial pneumonia-infected mice. For example, this combination treatment yielded a 3-fold increase in activation of the coagulation system pathway compared to MAb treatment alone (Fig. 4C).
A total of 13 different systemic antibacterials were used as empiric treatment in patients with viral pneumonia without bacterial coinfection for a total of 466 DOT. Vancomycin (50.7 %), cefepime (40.3 %), azithromycin (40.3 %), meropenem (23.9 %), and linezolid (20.9 %) were the most frequently used empiric antibacterials in patients with viral pneumonia without bacterial coinfection (Fig. 3). The most common regimens used in viral pneumonia without bacterial coinfection were vancomycin plus cefepime (28.4 %) and vancomycin plus meropenem (13.4 %). A total of 44 (65.7 %) patients with viral pneumonia without bacterial coinfection received empiric MRSA coverage with vancomycin or linezolid. Empiric antibacterial therapy was continued for a median of 4.1 days (interquartile range, 2.5–6.1 days) in viral pneumonia without bacterial coinfection, with most (69 %) being days on intravenous antibacterials.
Total antibacterial exposure differed between the long-course and short-course groups at 2116 and 484 DOT/1000PD, respectively (Fig. 3). Patients with mixed viral and bacterial infections received a total of 780 DOT/1000PD of systemic antibacterials. Median total antibacterial DOT/1000PD was also significantly higher in the long-course group compared with the short-course group (12.2 vs. 6.4; P <0.001) and the mixed-infection group (12.2 vs. 6.3; P <0.001). The most common antibacterials used were similar between groups: cefepime (long-course group: 73.1 %; short-course group: 50 %; mixed-infection group: 58.2 %), meropenem (long-course group: 37.3 %; short-course group: 32.1 %; mixed-infection group: 43.0 %), and linezolid (long-course group; 31.3 %; short-course group: 25 %; mixed-infection group: 41.7 %). Vancomycin was more commonly used in the long-course group compared with the mixed-infection group (80.6 vs. 59.5 %; P = 0.007) but not compared with the short-course group (80.6 vs. 57.1 %; P = 0.081). Azithromycin use was less prevalent in the mixed-infection group compared with the long-course group (48.1 % vs. 67.2 % of patients; P = 0.029) and the short-course group (48.1 vs. 71.4 %; P = 0.047).
For patient descriptions, we compared RSV-positive with RSV-negative patients within two groups of patients: all ARI patients and ARI patients with pneumonia. For the assessment of predictive factors for severity, patients with severe outcomes were compared with patients with no severe outcome within 6 groups of patients: all ARI patients, RSV-positive ARI patients, RSV-negative ARI patients, and those same three groups in patients less than 2-year old. Death, stay in ICU, oxygen use and severe pneumoniae were considered as indicators for severity. However, the mortality rate was too low to be analyzed and the analyses of ICU stay and oxygen use did not provide any added-value, so ultimately severe pneumonia alone was analyzed as an indicator of severe outcome. Data were double entered into an Access database (Microsoft Corporation). Statistical analysis was performed using Statistical Package for the Social Sciences version 23.0 for Windows (SPSS Inc., Chicago, IL, USA). For comparison of categorical data, the Pearson Chi-square (χ2) test and Fisher’s exact test were used as appropriate. The ANOVA test was applied to compare continuous variables. We fitted a binary logistic regression model, including a stepwise selection procedure, to assess predictive factors for severity. The level of significance was set at p < 0.05.
We described favorable clinical outcomes to antiviral therapy with cidofovir in non-immunocompromised adult patients with severe AdV pneumonia. Our data suggest that early administration of cidofovir in the course of treatment for respiratory failure as a result of AdV pneumonia in non-immunocompromised patients could be a treatment strategy worth considering, especially in cases of HAdV-55 infection.
The treatment and clinical outcomes between the severe and non-severe groups are compared in Table3. There were no significant differences in antimicrobial therapy, intensive care units, hemodialysis, and mechanical ventilation between the two groups. All patients from the two groups received the appropriate antibiotic therapy for pneumococcal pneumonia based on the antimicrobial susceptibility results. Twenty-three (12·0%) patients received antibiotics for pneumococcal pneumonia prior to arriving at this hospital, which was not significantly different between the case and the control groups (14 [14·1%] vs. 9 [9·8%], respectively; P = 0·355). The resistance rates of the pneumococcal isolates to penicillin and levofloxacin were significantly higher in the case group than in the control group (Table4).
The all-cause in-hospital mortality rate and pneumonia-related mortality rate were 8·4% and 6·3%, respectively. The median length of hospital stay for inpatients was 8 days (IQR, 4–18). Patients with severe pneumococcal pneumonia showed higher pneumonia-related mortality and longer hospital stays than patients with non-severe pneumococcal pneumonia (Table3).
The primary endpoint evaluated was in-hospital mortality. Secondary endpoints included hospital length-of-stay (LOS), intensive care unit (ICU) admission, and readmission rates at 30, 90, and 180 days after the index hospitalization.
Antibiotic resistance among clinical strains of S. pneumoniae underscores the urgency for alternative treatment strategies. Multimodal host- and pathogen-directed immunotherapy is a feasible option. Thus, we employed the experimental dual-infection mouse model to explore concurrent immunotherapy for secondary bacterial pneumonia. The host response protein cANGPTL4 and bacterial virulence factor pneumolysin were targeted using cognate neutralizing antibodies. The antipneumolysin antibody mitigated the pore-forming action of pneumolysin in human alveolar epithelial cells and reduced tissue damage. This effect persisted for 48 h (Fig. 4D). The concurrent antibiotic and antibody treatment significantly improved lung tissue integrity and, importantly, extended the median survival time of mice with secondary bacterial pneumonia compared to treatment with either the antibiotic or a single antibody (Fig. 4A and B). Taken together, these observations highlight that host-directed therapeutic anti-cANGPTL4 MAb can complement pathogen-directed treatment, such as conventional antibiotics or a novel antipneumolysin antibody, to enhance lung tissue integrity and augment host survival during secondary pneumococcal pneumonia. The improved tissue integrity and considerably longer median survival time suggest that a multimodal treatment approach targeting both host and pathogen factors can be highly efficacious against DRSP infection.
The following combination therapies may be performed. Anti-pneumococcal, anti-pseudomonal β-lactams, such as cefepime, piperacillin/tazobactam, imipenem, and meropenem may be used.
(a) Anti-pneumococcal, anti-pseudomonal β-lactam + ciprofloxacin or levofloxacin
(b) Anti-pneumococcal, anti-pseudomonal β-lactam + aminoglycoside + azithromycin
(c) Anti-pneumococcal, anti-pseudomonal β-lactam + aminoglycoside + anti-pneumococcal fluoroquinolone (gemifloxacin, levofloxacin, moxifloxacin)
The risk factors of P. aeruginosa infection include alcohol consumption, structural lung diseases such as bronchodilation, frequent use of steroids due to acute worsening of chronic obstructive pulmonary disease, and use of antibiotics in the last three months. If there is a possibility that a patient has pneumonia caused by P. aeruginosa, antibiotics that are effective against and highly sensitive to S. pneumoniae must be selected. Examples of these antibiotics include cefepime, piperacillin/tazobactam, imipenem, and meropenem. In a prospective observational study, gram-negative bacillus infections including those caused by P. aeruginosa were associated with high mortality rates. In a multi-institutional study conducted in Asian, gram-negative bacilli accounted for 10.1% of all cases of deaths, were the most common causative bacteria of severe pneumonia, and were a risk factor of death. Of these bacteria, P. aeruginosa may exhibit various levels of antibiotic resistance. Therefore, more than two empirical combination therapies are needed against these bacteria, and it is recommended to readjust the antibiotic selection once the bacteria are isolated and their susceptibility results are obtained.
(a) β-lactam+azithromycin or
(b) β-lactam+fluoroquinolone combination therapy is performed. The following antibiotics are recommended (in alphabetical order)
In a randomized controlled clinical trial involving patients with community-acquired pneumonia not accompanied by shock, combination therapy had no significant effects; however, the combination therapy showed better outcomes than the fluoroquinolone monotherapy for patients who were on mechanical ventilation. In another retrospective study, the β-lactam + macrolide combination therapy led to higher survival rates than the fluoroquinolone monotherapy for patients with severe pneumonia. Most patients who are admitted to an ICU experience shock, or require mechanical ventilation. Therefore, combination therapy is recommended over the fluoroquinolone monotherapy for these patients. The effectiveness of the fluoroquinolone monotherapy in pneumonia accompanied by meningitis caused by S. pneumoniae is unclear. In a recent noninferiority trial, the β-lactam + macrolide combination therapy produced better outcomes than the β-lactam monotherapy in severe pneumonia or pneumonia caused by atypical bacteria. In a prospective observational study involving patients with S. pneumoniae bacteremia, the combination therapy (β-lactam + macrolide or β-lactam + fluoroquinolone) also led to higher survival rates compared with the β-lactam monotherapy, and this result was observed not in patients with mild pneumonia, but patients with severe pneumonia. Some studies have also reported better treatment outcomes from combination therapy than from monotherapy even in patients treated with effective antibiotics. Therefore, for the empirical antibiotic treatment of patients with severe community-acquired pneumonia requiring ICU admission, combination therapy is recommended over monotherapy.
These have often been an intervention of last resort in the failing patient. Studies in meningitis and pneumocystis pneumonia support their role in infection control but, until recently, studies in community-acquired pneumonia were absent. The conflicting results from studies in sepsis confirmed the need for community-acquired pneumonia-specific studies, preferably randomised controlled trials. A recent double blind, placebo-controlled randomized controlled trial using 40 mg prednisolone for 7 days as the intervention found that there were no beneficial effects of adjunctive corticosteroids in patients hospitalized with community-acquired pneumonia. Other outcomes of the study showed that clinical cure was equal in both groups at Day 7. A similar study using dexamethasone for 3 days did find a reduced hospital stay of one day in the steroid-treated patients, but a large number of exclusions and lack of control for other factors limiting length of stay limited the usefulness of this study. The only other randomised controlled trial evaluating patients with community-acquired pneumonia admitted to ICU found a reduction in mortality using hydrocortisone. The small patient number and absence of any deaths in the intervention arm mean that these findings cannot be generalised unless reproduced in other studies. A role for steroids in patients with community-acquired pneumonia is yet to be proved.
The crude odds ratio (OR) of exposure was calculated to assess the relative frequency of detection of each respiratory pathogen among cases and controls. Multivariate logistic regression was used to calculate the adjusted OR (aOR) of detection of each pathogen for cases versus controls, adjusting for underlying demographic differences, recent exposure to antibiotics and for the presence of other pathogens. The aOR for each pathogen was then used to estimate the population-attributable fraction (PAF).26 Analyses were performed using STATA software, V.13.0, and figures were produced using GraphPad Prism, Version 5.0 (GraphPad Software, California, USA).
The last few years have seen some major advances in the management of community-acquired pneumonia. Risk stratification of patients has recently been advanced by the addition of several useful biomarkers. The issue of single versus dual antibiotic treatment remains controversial and awaits a conclusive randomized controlled trial. However, in the meantime, there is a working consensus that more severe patients should receive dual therapy.
This research was submitted to our university institutional review board and was
approved. The IRBNet ID is 1083099-2.
The pneumococcal conjugate vaccination and Haemophilus influenzae type B conjugate vaccination have been effective tools to decrease pneumonia incidence, severity and mortality [58, 59]. However, equitable coverage and access to vaccines remains sub-optimal. By the end of 2015, Haemophilus influenzae type B conjugate vaccination had been introduced in 73 countries, with global coverage estimated at 68%. However, inequities are still apparent among regions: in the Americas coverage is estimated at 90%, while in the Western Pacific it is only 25%. By 2015, pneumococcal conjugate vaccination had been introduced into 54 countries, with global coverage of 35% for three doses of pneumococcal conjugate vaccination for infant populations. To address this issue, the WHO’s Global Vaccine Access Plan initiative was launched to make life-saving vaccines more equitably available. In addition to securing guarantees for financing of vaccines, the program objectives include building political will in low- and middle-income countries to commit to immunization as a priority, social marketing to individuals and communities, strengthening health systems and promoting relevant local research and development innovations.
Maternal vaccination to prevent disease in the youngest infants has been shown to be effective for tetanus, influenza and pertussis. Influenza vaccination during pregnancy is safe, provides reasonable maternal protection against influenza, and also protects infants for a limited period from confirmed influenza infection (vaccine efficacy 63% in Bangladesh and 50.4% in South Africa). However as antibody levels drop sharply after birth, infant protection does not persist much beyond 8 weeks. Recently respiratory syncytial virus vaccination in pregnancy has been shown to be safe and immunogenic, and a phase-3 clinical trial of efficacy at preventing respiratory syncytial virus disease in infants is under way. Within a decade, respiratory syncytial virus in infancy might be vaccine-preventable, with further decreases in pneumonia incidence, morbidity and mortality.
Improved access to health care, better nutrition and improved living conditions might contribute to further decreases in childhood pneumonia burden. The WHO Integrated Global Action Plan for diarrhea and pneumonia highlights many opportunities to protect, prevent and treat children. Breastfeeding rates can be improved by programs that combine education and counseling interventions in homes, communities and health facilities, and by promotion of baby-friendly hospitals. Improved home ventilation, cleaner cooking fuels and reduction in exposure to cigarette smoke are essential interventions to reduce the incidence and severity of pneumonia [70, 71]. Prevention of pediatric HIV is possible by providing interventions to prevent mother-to-child transmission. Early infant HIV testing and early initiation of antiretroviral therapy and cotrimoxazole prophylaxis can substantially reduce the incidence of community-acquired pneumonia among HIV-infected children. Community-based interventions reduce pneumonia mortality and have the indirect effect of improved-care-seeking behavior. If these cost-effective interventions were scaled up, it is estimated that 67% of pneumonia deaths in low- and middle-income countries could be prevented by 2025.
Several clinical trials of antibiotics for CAP are registered on ClinTrialsGov.
A study in Beijing Children’s Hospital (NCT02775968) is investigating the population pharmacokinetics of cephalosporins and macrolide antibiotics for CAP in children, aiming to correlate it with treatment effectiveness and the incidence of adverse effects. The study commenced in August 2016 with an estimated enrollment of 750 children and a completion date of October 2022.
A phase 2/3, randomised, open-label, active control, multi-centre study (NCT02605122) to assess the safety and efficacy of solithromycin in children and adolescents with CAP is being conducted under the sponsorship of Cempra Inc.. Solithromycin will be compared with the standard of care for an estimated enrollment of 400 patients. The study commenced in March 2016 with an estimated completion date of January 2018.
A Canadian randomised, controlled, double-blind, non-inferiority clinical trial (NCT02380352) will determine whether 5 days of high-dose amoxicillin leads to comparable rates of early clinical cure compared with 10 days of high-dose amoxicillin for previously healthy children with mild CAP. In the experimental arm, patients will be given 5 days of amoxicillin 90 mg/kg/day in three divided doses, followed by 5 days placebo three times a day. The active comparator arm will be given 5 days amoxicillin 90 mg/kg/day in three divided doses, followed by alternate formulation 5 days amoxicillin 90 mg/kg/day in three divided doses. The estimated enrollment for the study is 270 patients and it commenced in March 2016 with a completion date of May 2018.
The National Institute of Allergy and Infectious Diseases (NIAID) is sponsoring a multi-centre, randomised, double-blind, placebo-controlled, superiority clinical trial (NCT02891915) to test the effectiveness of short (5-day) vs standard (10-day) course therapy in children diagnosed with CAP and initially treated in outpatient clinics, urgent care facilities and emergency departments. The primary objective is to compare the composite overall outcome (Desirability of Outcome Ranking, DOOR) in children with CAP aged 6–71 months assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient β-lactam therapy at Outcome Assessment Visit 1 (Study Day 8 ± 2 days). The study commenced in October 2016 and the completion date is March 2019 with an estimated enrollment of 400 patients.
A Malaysian trial (NCT02258763) in children hospitalised with pneumonia is being conducted to determine whether an extended duration of oral antibiotics (10 days) is better for improving clinical outcomes than a shorter duration (3 days) of antibiotics. Patients in the experimental arm will receive amoxicillin-clavulanate 22.5 mg/kg/dose bd for 10 days, while the comparator arm will receive amoxicillin-clavulanate 22.5 mg/kg/bd for 3 days followed by another 7 days of placebo given at the same dose and frequency. The study began in November 2014, aiming to enrol 300 patients, and the estimated completion date is December 2018.
Two clinical trials investigating amoxicillin in childhood pneumonia are being conducted in Malawi. In a trial (NCT02760420) sponsored by Save the Children, the effectiveness of no antibiotic treatment for fast-breathing CAP is being compared with amoxicillin therapy. Patients in the placebo arm will be given 250 mg of placebo (dispersible tablet) in two divided doses based on age bands (500 mg/day for children 2–12 months, 1000 mg/day for children 12 months to 3 years, and 1500 mg/day for children 3–5 years of age). The active comparator arm will receive 3 days of 250 mg amoxicillin, dispersible tablet (DT) in two divided doses based on age bands (500 mg/day for children 2–12 months, 1000 mg/day for children 12 months to 3 years, and 1500 mg/day for children 3–5 years). The estimated enrollment is 2000 patients with the study running from June 2016 to September 2018.
In the same setting, another trial (NCT02678195) will compare 3 vs 5 days of treatment for chest-indrawing pneumonia. The experimental arm will receive 3 days of amoxicillin and 2 days of placebo while the comparator arm will receive 5 days of amoxicillin. The study aimed to run from March 2016 to August 2018 with an estimated enrollment of 2000 patients.
A one-arm safety intervention (NCT02878031) in Nigeria will evaluate the role of community management of chest-indrawing pneumonia with oral amoxicillin. The primary objective is to assess whether community health workers can safely and appropriately manage chest-indrawing pneumonia in children aged 2–59 months and refer children with danger signs. The aim was to include approximately 308 children aged 2–59 months with chest-indrawing pneumonia and the study was conducted between October 2016 and July 2017.
In a double blind efficacy study entitled RETAPP (NCT02372461), investigators based at Aga Khan University, Karachi compared standard amoxicillin treatment with placebo in poor urban slum settings in South Asia. The study ran from November 2014 to July 2017 with an enrolment of 2500 patients.
Investigators in the United Kingdom are initiating a multi-centre, randomised, double-blind placebo-controlled 2 × 2 factorial non-inferiority trial of amoxicillin dosage and duration in paediatric CAP (CAP-IT) (ISRCTN76888927). The efficacy, safety and impact on antimicrobial resistance related to the duration and dosage of amoxicillin will be assessed in children aged 1–5 years presenting to the Emergency Room or Paediatric Assessment Unit with a clinical diagnosis of CAP in whom the decision has been made to treat with antibiotics. Participants will be randomised to four treatment groups: shorter course and lower dose (3 days of 35–50 mg/kg/day), longer course and lower dose (7 days of 35–50 mg/kg/day), shorter course and higher dose (3 days of 70–90 mg/kg/day), and longer course and higher dose (7 days of 70–90 mg/kg/day). They expect to recruit 2400 over the 2 years from March 2016 to May 2018.
Several previous studies have revealed potential morbidity from bacterial pneumonia
in patients with respiratory syncytial virus (RSV). RSV infection may increase the
risk for pneumococcal pneumonia.1 RSV increases the virulence of streptococcal pneumonia by binding to
penicillin-binding protein 1a. Coinfection with RSV and Streptococcus
pneumoniae is associated with severe and often fatal pneumonia.2 Physicians must be mindful of the potential for secondary bacterial pneumonia
in viral bronchiolitis so that it can be promptly treated.
As pediatricians, we follow the guidelines published by the American Academy of
Pediatrics. The 2014 guidelines dealing with evaluation and management of viral
bronchiolitis promote supportive care, and note that routine radiographic or
laboratory studies are not necessary.3 While these guidelines are paramount to treating viral illness, it is
imperative that the physician recognizes at what point further investigation is
warranted. Missing a secondary pneumonia could result in delay in antibiotic
treatment, transfer to the pediatric intensive care unit (PICU), or intubation.
Following a respiratory season at our institution, we noted that children with viral
illness who also had a fever tended to have a worse clinical course versus afebrile
patients. We hypothesized that fever may be a marker for secondary bacterial
pneumonia in patients with viral bronchiolitis. Fever is defined as temperature
≥100.4°F. If a patient developed a fever and the workup showed pneumonia, then
antibiotics could be started quickly rather than waiting until after worsening of
the patient’s clinical condition. Our hypothesis is based on the following anecdotal
evidence from our practice:
Our objective is to investigate whether children with viral bronchiolitis with fever
are more likely to have a diagnosis of secondary bacterial pneumonia than their
counterparts without fever.