CIDRAP ASP Journal Club - March 2017

Dassner AM, Nicolau DP, Girotto JE. Management of pneumonia in the pediatric critical care unit: an area for antimicrobial stewardship. Curr Pediatr Rev 2016 (published online Dec 4)

Our journal club for March 2017 will focus on the issue of diagnostics, etiology, and antimicrobial dosing for severe pediatric pneumonia, and there will be several ways to share your thoughts on the research and your experiences in clinical practice, learn from experts involved in clinical pharmacy and pharmacokinetic monitoring, and join a conversation about the implications of this study.

There are multiple ways to participate!

Read the article or the summary below, along with comments that have already been posted.

Listen to our podcast with study authors Aimee M. Dassner, PharmD, and Jennifer E. Girotto, Pharm D, of Connecticut Children’s Medical Center.

Comment on the study or on any issue you feel is important to the topic of antimicrobial stewardship in the treatment of severe pediatric pneumonia. Please feel free to also answer any of the questions below the summary. Comments are submitted via e-mail and posted when appropriate to ensure a respectful conversation.

View the Storify stream of our March 16 Twitter chat with Jennifer Girotto, PharmD, and Aimee Dassner, PharmD.

Tweet your comments on the study and/or the issue any time during March. Make sure to include our handle (@CIDRAP_ASP) and the hashtag #ASPJournalClub.

Article summary

Why is this topic important?

Pediatric pneumonia is one of the most common causes of childhood infection requiring hospitalization and antimicrobial use.1-3 Approximately 12% to 20% of children hospitalized with community-acquired pneumonia (CAP) require critical care, with children ages 1 to 6 years most likely to require intensive care.1, 4, 5 Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are responsible for 15% to 53% of hospital-associated infections and are the most common indication for empiric antibiotic therapy in the pediatric intensive care unit (PICU).6-8

Optimizing appropriate antimicrobial therapies for children with pneumonia hospitalized in the PICU is stymied by ill-defined definitive diagnostic criteria, difficulty in differentiating between viral and bacterial sources in children, and inconsistent or a lack of dosing guidelines that consider the specific pharmacodynamics and pharmacokinetics of critically ill children.

The treatment of pediatric pneumonia is a significant area for antimicrobial stewardship interventions that improve patient outcomes while reducing inappropriate antimicrobial use and resistance and improving the selection and maintenance of appropriate antibiotic therapy. 

What were the goals of the study?

The goal of the literature review is to highlight the role of antimicrobial stewardship efforts in the treatment of pneumonia in critically ill children by discussing: (1) emerging diagnostic criteria; (2) the etiology of disease in pediatric CAP, HAP, and VAP; (3) appropriate targeted antimicrobial selection; and (4) the optimization of antibiotic dosing in children.

What methods did the authors use?

The authors conducted a literature review of 132 studies and guidelines published from 1990 to 2016. 

What did they find? 

Diagnostic criteria

Diagnostic tools for pneumonia in critically ill children involve radiologic tests, microbiologic cultures, molecular diagnostics, and examination of acute-phase reactants and candidate biomarkers. Each method is associated with a varying degree of sensitivity and specificity, along with an unpredictable ability to identify the causative pathogen, in the pediatric population.

Confirmatory chest radiography is recommended for all critically ill children when pneumonia is suspected, and chest x-rays may give insight into disease severity if factors like involvement of multiple pulmonary sites or upper lobe involvement can be determined.

Radiography may also assist clinicians in identifying whether the causative pathogen is bacterial or viral; one study showed an association between upper lobe infiltrates and pleural effusion on x-ray and pneumonia caused by Streptococcus pneumoniae.11 However, radiography has been shown to be only modestly helpful in distinguishing between bacterial and viral pneumonia in children.

Diagnostic criteria for HAP and VAP require two or more serial chest images, though patients without an underlying pulmonary or cardiac condition require only one definitive x-ray.12 The authors found, however, that specificity of radiography is only 33% to 42% in intubated children, making it a difficult decision support tool in the PICU.13 

Microbiologic diagnostics
Microbiologic diagnostics for critically ill children with pneumonia include blood, pleural fluid, and sputum cultures. National guidelines recommend obtaining blood cultures for children requiring hospitalization for CAP and complicated bacterial pneumonia, recognizing that the incidence of bacteremia is higher in children with severe CAP who have empyema, have effusion, or require PICU admission.14 The authors cite a meta-analysis that reported a blood culture positivity rate of 9.9% among 2,794 patients with severe pneumonia.15 Limitations to blood culturing include the significant incidence of contaminants.

Pleural fluid cultures have a low sensitivity rate if antibiotics have been administered to the patient prior to obtaining the specimen. Additionally, blood and pleural fluid cultures may not result in identification of a causative pathogen. In a multicenter study of pediatric patients with pneumonia, 18% of pleural fluid cultures identified a pathogen, compared with 12% of blood cultures, and 9% of cases in which both tests returned a result.5

Sputum cultures are generally used only in children who are intubated and ventilated; in other cases, sputum is unlikely to provide a quality specimen for accurate diagnosis. Sputum culture has a low specificity, especially in the diagnosis of VAP and may be inconsistent with clinical and radiographic VAP diagnostic criteria. Tracheal aspirate cultures (TACs) are commonly used to obtain material for culture, but results have a low specificity, and using this approach could lead to antibiotic overuse.14

Molecular diagnostics
Real-time polymerase chain reaction (RT-PCR) tends to yield sensitive results within hours, allows for simultaneous identification of multiple pathogens, and can identify pathogens in complicated bacterial pneumonia that may be culture-negative in up to 60% of cases.5,16 A Canadian study of 56 children with pneumonia found that multiplex RT-PCR (mRT-PCR) identified bacteria in 82% of parapneumonic effusion fluids compared with 25% identified in culture-based sampling.4 In a study of 63 children, 73% of culture-negative parapneumonic effusion pleural fluid specimens had a pathogen identified by mRT-PCR.16

Rapid molecular identification of viral pathogens can prevent or stop unnecessary antibiotic therapy. In one study of 4,779 children, use of mRT-PCR was associated with a shorter median duration of antibiotic use, fewer radiographs during the first 2 days of admission, and more patients on isolation precautions compared with enzyme immunoassay, direct fluorescent antigen, PCR, and viral cultures.17 Another analysis of 1,727 children hospitalized for upper respiratory infections found that mRT-PCR identified a causative virus in 706 out of 809 specimens tested (87%), which prevented unnecessary antibiotic therapy.17

The Infectious Diseases Society of America (IDSA) recommends the use of RT-PCR for identification of suspected Mycoplasma pneumoniae infection in addition to single-sample serology testing.14 However, providers should be wary of positive results in patients who are asymptomatic carriers of M pneumoniae.

Acute-phase reactants and candidate biomarkers
Acute-phase reactants, such as C-reactive protein (CRP) and procalcitonin (PCT), and candidate biomarkers, such as proadrenomedulin and copeptin, can distinguish between viral and bacterial pneumonia, indicate disease severity, and guide the duration of antibiotic use.  Available data suggest that CRP and PCT have similar positive predictive values (90% for CRP and 88% for PCT), but PCT has a higher negative predictive value (75% for PCT vs 57% for CRP); inspiring greater confidence in a negative result.41

The candidate biomarkers proadrenomedullin and copeptin may distinguish severity of disease, but additional study of these biomarkers is needed to clarify their utility.

Etiology of disease

CAP in the critically ill pediatric patient
Viral pneumonia is the most common cause of CAP in children, especially in those under 2 years old. Data from the Severe Influenza Pneumonia Surveillance Project showed that 19% of 75 children hospitalized in the critical care unit were infected with at least one virus.21 A meta-analysis published in 2010 of 2,794 patients with severe CAP found that the following pathogens were the most common bacterial agents: S pneumoniae infection in 97.1%, Haemophilus influenzae in 1.4%, and Klebsiella pneumoniae in 1%.15  A study published in 2013 identified S pneumoniae and Staphylococcus aureus as the primary bacterial pathogens causing CAP, a shift likely explained by the introduction of the pneumococcal and H influenzae vaccines.5M pneumoniae is a more common cause of CAP in adolescents (23%) than in children less than 5 years old (<5%).1

The authors of the current study found that a viral-bacterial co-infection had a significant effect on pediatric pneumonia severity and noted, therefore, that the decision not to use antibiotics should not be based on viral identification alone. Additionally, Panton-Valentine leukocidin (PVL)–producing community-acquired methicillin-resistant S aureus (MRSA) may cause complicated pneumonia frequently in the context of influenza co-infection.

Empiric antimicrobial therapy for treatment of severe pediatric CAP should provide coverage of all likely pathogens. Antimicrobial use should be determined based on patient symptoms, disease severity, and likely pathogens, with coverage limited to the narrowest effective antibiotic. No randomized controlled trials have evaluated duration of therapy in critically ill children, though a 10-day course of therapy is standard for pneumonia caused by S aureus, and complicated pneumonia may require treatment for up to 4 weeks.

  • When bacterial pneumonia is suspected, IDSA recommends that fully immunized children without empyema be treated with ampicillin as first-line therapy with dosing based on local S pneumoniae resistance rates (ie, a range of 150 to 400 mg/kg/day divided every 6 hours). For patients who are under-immunized or who present with empyema, guidelines recommend empiric cefotaxime (150 mg/kg/day divided every 8 hours) or eftriaxone (100 mg/kg/day divided every 12 to 24 hours).14

  • IDSA guidelines for empiric treatment to target MRSA pneumonia recommend vancomycin within a range of 10 to 15 mg/kg/day every 6 hours. Alternatives to vancomycin include clindamycin delivered at a dose of 40 mg/kg/day divided every 6 to 8 hours when less than 10% MRSA resistance is evident, or linezolid delivered at 30 mg/kg/day divided every 8 hours for children under 12 years and 600 mg/kg/day divided every 12 hours for children 12 and older.14, 23

  • In cases of M pneumoniae, the value of macrolide use is controversial. IDSA recommends oral azithromycin at 10 mg/kg/day for 1 day followed by 4 days of 5 mg/kg/day for children older than 7 years, though the literature provides little evidence of clinical benefit from treatment targeted toward M pneumoniae.14

Nosocomial pneumonia in the critically ill pediatric patient
Diagnosis of HAP and VAP in children can be difficult owing to varying diagnostic definitions and clinical signs. Though, data on risk factors for nosocomial pneumonia in children are limited, two studies found that pediatric risk factors include use and duration of mechanical ventilation, male sex, older age (16 to 18 years), higher injury scores, longer duration of ICU stay, sedation, nasogastric feeds, H2 blockers, and gastroesophageal reflux disease.24,25 In addition, causes of HAP and VAP in children may vary, depending on age, local epidemiology, and duration of mechanical ventilation. Optimal duration of therapy for HAP and VAP in children is undefined, and adult data are typically applied (7 to 8 days, with 10 to 15 days considered for patients who do not improve and patients with non-lactose fermenting pathogens such as Pseudomonas spp and Acinetobacter spp).

In cases of HAP where access to accurate specimen collection is limited, antimicrobial therapy remains empiric unless the pathogen can be identified via blood culture. In cases of VAP, pneumonia etiology has been associated with the duration of mechanical ventilation, with S pneumoniae, S aureus, and H influenzae predominating in the first 4 to 5 days. Later-onset VAPs are often caused by antibiotic-resistant S aureus and gram-negative nosocomial pathogens such as P aeruginosa, E coli, Enterobacter spp, and Acinetobacter spp.26-28 Because children are often colonized by bacteria in the lower respiratory tract, a single causative pathogen may not always be identified.

National clinical guidelines and outcomes data evaluating treatment regimens for pediatric HAP and VAP are lacking, but the authors recommend that nosocomial pneumonia in children be treated similarly to severe CAP by using broad-spectrum antibiotics within the first few days of hospitalization and considering local antibiotic susceptibilities. Key points highlighted include:

  • Vancomycin is often used in combination with a gram-negative agent to provide coverage for S aureus.

  • Initial empiric therapy with piperacillin/tazobactam, cefepime, or levofloxacin can provide coverage against susceptible gram-negative bacteria and methicillin-susceptible S aureus.

  • Ceftazidime and ciprofloxacin can provide broad spectrum gram-negative coverage, but lack adequate gram-positive activity.

  • Additional considerations are necessary when coverage for resistant organisms is needed.

    • Possible options for coverage of AmpC-producing Enterobacteriaceae include cefepime, a fluoroquinolone, or a carbapenem.

    • A carbapenem can be used to cover extended-spectrum beta-lactamase (ESBL)–producing organisms.

    • Combination therapy including a carbapenem and an aminoglycoside or colistin may be used for resistant gram-negative bacteria.

    • Ceftazidime/avibactam and ceftolozane/tazobactam provide broad-spectrum coverage for children at risk of multidrug-resistant gram-negative infections, but pediatric data are lacking for these agents. 

The use of anti-pseudomonal carbapenems and broad-spectrum antibiotics should be carefully considered in children, with patients’ risk of multi-drug resistant organisms stratified based on comorbidities, history of antibiotic exposure, length of hospitalization, local resistance patterns, and an understanding of common colonizers in children. In a study of risk stratification, researchers found a 33% decrease in broad-spectrum antibiotic days of therapy per 1,000 patient days over 12 months with no change in critical care unit mortality rates.29

Optimizing Antimicrobial Pharmacodynamics

Limited data are available regarding dosing and pharmacodynamics in children with pneumonia, and the authors agree that therapeutic dosing should be based on response to antimicrobial therapy, availability of monitoring, and calculation of patient-specific pharmacokinetic parameters.

The efficacy of beta-lactams is described by time-dependent pharmacodynamics, and optimization is the function of the percent time of serum-free drug concentration (SFDC) above the minimum inhibitory concentration (MIC) for a pathogen (eg, carbapenems have bactericidal activity at 40% SFDC>MIC, penicillins at 40% to 50% SFDC>MIC, and cephalosporins at 50% to 70% SFDC>MIC).30-33

Strategies for optimizing beta-lactam dosing include ensuring an adequate mg/kg dose, decreasing the dosing interval, and increasing infusion duration to maintain serum drug concentrations and optimal bactericidal activity. Available data suggest that dosing regimens targeting higher MICs should be used in children with severe pneumonia.

The efficacy of vancomycin is defined by its area-under-the-curve (AUC)/MIC ratio. For treatment of MRSA, IDSA recommends 45 to 60 mg/kg/day divided every 6 hours to target a trough of 15 to 20 mcg/mL.23

Dosing in children with severe pneumonia should be based on an understanding of local MIC data to determine appropriate targets and should balance pharmacodynamics with the risk of nephrotoxicity, which may be predicted by duration of vancomycin therapy, vasopressor use, and pharmacokinetic indices.

The efficacy of clindamycin against MRSA is defined by its AUC/MIC ratio and the optimization of its prolonged post-antibiotic effect. Available data suggest that optimal dosing is 10 to 13 mg/kg every 6 to 8 hours for a maximum of 40 mg per day.34

Linezolid exhibits concentration-dependent bactericidal pharmacodynamics, though few studies have evaluated dosing optimization in children. Younger children clear linezolid faster than adolescents and adults do, so age-related pharmacokinetic monitoring is required. Current recommendations suggest 30 mg/kg/day divided every 8 hours for children under 12 years, and 600 mg every 12 hours for children 12 and older.35 Several studies, however, have shown that standard doses may not be adequate in achieving killing of S pneumoniae or S aureus with an MIC of 2 mg/L or greater owing to inter-patient pharmacokinetic differences that may affect achievement of pharmacodynamic targets.36

The bactericidal activity of fluoroquinolones is concentration-dependent, and the American Academy of Pediatrics suggests that their use can be considered for the treatment of infections with no safe alternative, such as severe pneumonia caused by resistant organisms.12

Pharmacodynamic data on levofloxacin use in children are limited. Total body clearance of levofloxacin varies significantly between children and adults and also varies as a result of age in children under 10 years. Based on several pharmacokinetic studies, the authors stated that levofloxacin in unlikely to attain adequate exposure for the treatment of severe pneumonia in children caused by susceptible S pneumoniae isolates with an MIC greater than 1mg/L. They also noted that levofloxacin likely would not achieve the pharmacodynamic AUC/MIC breakpoint of 125 at the MIC breakpoint of 2 mg/L. 37

Ciprofloxacin does not offer reliable S pneumoniae coverage, so its use is specific to activity against gram-negative pathogens. The efficacy of ciprofloxacin is linked to an AUC/MIC of 125. Additionally, it does not provide optimal coverage up to the susceptibility breakpoint of 1 mg/L for Enterobacteriaeae, Pseudomonas spp, and Acinetobacter spp 38

The aminoglycosides gentamicin, tobramycin, and amikacin exhibit concentration-dependent killing and a post-antibiotic effect. Because of the risk of nephrotoxicity and ototoxicity associated with prolonged exposure, optimization should maximize concentration-dependent killing while minimizing the risk of drug accumulation via once-daily or extended-interval dosing.

Though aminoglycosides play an important role in the treatment of multidrug-resistant gram-negative pneumonia, few studies have evaluated once-daily dosing in the PICU. A survey of 75 children’s hospitals found that 62.7% used once-daily dosing, and 54.7% use it all or most of the time, although the most commonly reported reason for not using the tactic was lack of data supporting efficacy in children (55.6%).39 If once-daily dosing is used, therapeutic drug monitoring should ensure peak serum concentrations, sufficient clearance, and appropriate duration of therapy.

Colistin exhibits concentration-dependent bactericidal activity with efficacy dependent on an adequate AUC/MIC ratio. Pediatric data evaluating intravenous colistin in combination with other antibiotics in the ICU appear promising, but optimal dosing strategies to optimize bactericidal efficacy while minimizing nephrotoxicity and neurotoxity remain undetermined in critically ill children. US labeling recommends 2.5 to 5 mg/kg/day administered intravenously in 2 to 4 divided doses.

What are the major study limitations?

The literature review was limited to studies addressing antimicrobial treatment of community-acquired and nosocomial pneumonia in critically ill children. Data are limited regarding the sensitivity and specificity of diagnostics, along with their ability to identify pathogens, causes of pneumonia in different settings and age-groups, and dosing strategies for children that effectively treat infection while minimizing risk of toxicity. In many cases, dosing guidelines were extrapolated from adult optimal pharmacodynamic ranges or from studies examining antimicrobial dosing in children with cystic fibrosis or pulmonary infections other than pneumonia.

What are the practice and policy implications?

Antimicrobial stewardship in the critical care response to pediatric pneumonia is complicated by ill-defined diagnostic criteria, difficulty differentiating between disease causes, and limited data on optimal dosing and pediatric pharmacokinetics. Stewardship programs should incorporate an evidence-informed understanding of diagnostic tests, likely pathogens and local susceptibility data, and dosing strategies that optimize pharmacodynamics while minimizing toxicity.

Topics for discussion: Your feedback welcome!

What are the biggest challenges in optimizing antimicrobial treatment for pediatric pneumonia?

How can researchers and clinicians address the limited outcomes data available for dosing pharmacodynamics in children?

Do you believe that current pneumonia causes and susceptibilities have changed since the introduction of the 9- and 13-valent pneumococcal vaccine and the H influenzae vaccine?

How helpful are local pediatric antibiograms and susceptibility reports for the appropriate treatment of severe pneumonia?

Have you implemented treatment strategies that align or differ with those mentioned in the literature review? What practices worked, and what proved to be challenging? What data or experience informed your decisions?


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