Challenges in pediatric infectious diseases

Issue: September 2016

ByLeah Molloy, PharmD

The management of infectious diseases in children involves many of the same therapeutic principles seen in adult medicine, but it is also complicated by challenges unique to this special patient population. These include a relative lack of evidence-based consensus guidelines, fewer agents approved by the FDA for use in children, altered pharmacokinetic parameters and unique drug toxicities. While these challenges call for extra effort and diligence, they also present unique opportunities to optimize antimicrobial therapy.

Consensus guideline recommendations

Prior to the 2011 guideline for community-acquired pneumonia (CAP) in children, the Infectious Diseases Society of America (IDSA) had no pediatric-specific practice guidelines. Before then, some IDSA guidelines (eg, bacterial meningitis, intra-abdominal infections) included pediatric recommendations, but others (eg, urinary tract infections, vancomycin) were specific to adult patients only. Potential reasons for this relative lack of treatment guidelines for children may include less availability of controlled trials and a subsequent greater reliance on case reports and personal experience. Fortunately, the American Academy of Pediatrics (AAP) has a number of treatment guidelines specific to children, and the IDSA and other organizations continue to incorporate pediatric data into recommendations, but these strides have not come without limitations. For example, the 2015 American Heart Association guideline to treat infective endocarditis in children has been criticized for its suboptimal antimicrobial dosing recommendations, potentially owing to the absence of a pediatric pharmacist from the author panel.

Approved indications and doses

Fewer antimicrobial agents are approved for use in children than adults. Labeled indications for children typically lag behind, and clinical necessity often forces off-label use of medications while awaiting sufficient data to support an FDA-approved indication. For example, Mycamine (micafungin, Astellas Pharma) initially was approved for use in adult patients in the United States in 2005, but pediatric indications and dosing recommendations were not approved and incorporated into the package insert until 2013. As multidrug-resistant gram-negative infections continue to be reported among children, the absence of pediatric provisions for recently approved, novel agents like Avycaz (ceftazidime/avibactam, Allergan) and Zerbaxa (ceftolozane/tazobactam, Merck) leaves clinicians with the same unfavorable alternative options like Tygacil (tigecycline, Pfizer) and colistin.

Legislation to support — or in some cases mandate — pediatric drug studies has been enacted. These include the Best Pharmaceuticals for Children Act, which grants prolonged patent exclusivity to manufacturers completing FDA-requested pediatric research, and the Pediatric Research Equity Act, which can require companies to research their product in children. Pursuant to these acts and subsequent approvals, fewer medications are being used off-label in children.

Pharmacokinetic alterations

Determination of appropriate dosing strategies is complicated by unique pharmacokinetic (PK) parameters observed among children, and medications prescribed in weight-based doses for adult patients do not necessarily translate to doses appropriate for children. For example, newborns require gentamicin doses as high as 4-5 mg/kg to reach peak serum concentrations comparable to those attained with doses of only 2 mg/kg in adult patients. While this increased dose requirement is well-understood and incorporated into routine practice, such differences also exist for other medications that are not as well-characterized in children.

Cubicin (daptomycin, Merck) is approved for indication-specific doses of 4-6 mg/kg for adults, but drug exposures are significantly lower among children receiving the same weight-based dose. A single-dose PK study of 4 mg/kg yielded a mean area under the concentration-time curve (AUC) of only 215 mcghr/mL for children aged 2 to 6 years, compared with 374 mcghr/mL among children aged 12 to 17 years (P < .05), and these were generally lower than previously reported AUC values in adult patients, ranging from 300 mcghr/mL to over 500 mcghr/mL. Some of these differences may be attributed to the substantially faster rate of daptomycin elimination observed in young children vs. adolescents and adults. In accordance with the conclusion that higher doses are likely needed for younger patients, daptomycin is currently being studied in children with acute hematogenous osteomyelitis at higher weight-based doses ranging from 7-12 mg/kg. While awaiting these results, clinicians using weight-based doses approved for adults will likely substantially underdose their patients, though the AAP and other pediatric dosing references offer some early guidance for more appropriate dosing. Further complicating dose determination is the common use of high-dose daptomycin (8-10 mg/kg) in adult patients with severe infections. Attainment of similar drug exposures in children could require much higher doses.

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Identifying appropriate dosing strategies has important clinical implications for efficacy and safety, but also for the prevention of antimicrobial resistance. Development of antimicrobial resistance among children with cystic fibrosis (CF) after receiving repeated courses of antibiotics has been reported, specifically resistance of Staphylococcus aureus to linezolid and Teflaro (ceftaroline fosamil, Allergan). Authors of those reports acknowledge that inadequate drug exposure likely contributed to drug resistance. These experiences re-emphasize from a different perspective the need for better PK data and dosing recommendations not only for children in general, but also for special populations like CF.

Unique drug toxicities

In addition to fewer available FDA-approved indications and dosing recommendations, options are more limited in children owing to unique drug toxicities. While some pediatric-specific drug toxicities are well-known and generally excluded from practice, blind avoidance without consideration of the clinical situation and a balanced comparison of risks and benefits can also be dangerous. A classic example is the management of Rocky Mountain spotted fever (RMSF). The preferred treatment of RMSF is doxycycline, known to cause permanent tooth discoloration in children aged younger than 8 years and thus avoided in this age group in accordance with package insert warnings. However, because of the superior efficacy of doxycycline compared with alternative antibiotics, the CDC and AAP still recommend its use for RMSF in children of all ages. Unfortunately, there remains a significantly higher case-fatality rate among young children afflicted with RMSF compared with older patients, which may be related to physician hesitancy to prescribe doxycycline. One study published in 2015 found no difference in tooth color or development among children who had received doxycycline before age 8 years compared with a doxycycline-naive comparator group. The researchers concluded that doxycycline can be used without hesitation in these cases and called for a revision to the package insert recommending the same.

Antimicrobial stewardship methods and metrics

Pediatric antimicrobial stewardship (AS) has been an area of much discussion and growth, with ongoing practice expansion. The encouragement to apply general AS concepts to pediatric populations with specific recommendations to practice AS within the neonatal ICU are important additions to the 2016 update to the IDSA guideline for AS. Additionally, in contrast to the 2007 guideline, which recommends the use of defined daily doses (DDDs) as a standardized antimicrobial use metric for reporting and benchmarking, the revised guideline recommends using days of therapy (DOTs) for all patient populations. This is important for pediatric AS because DDDs, calculated by dividing total grams of a given antimicrobial agent by the typical adult daily dose, are an inaccurate marker of drug exposure in children. The recommended DOT metric more accurately reflects antimicrobial consumption in all patient populations.

Unique opportunities

Owing to different types of infections and causative pathogens, unique opportunities exist for AS interventions tailored to children that could not be as readily applied to adult patients. For example, the IDSA guideline for CAP in otherwise healthy children recommends treatment with ampicillin instead of ceftriaxone, which previously had been a standard approach and continues to be used for adult patients. Upon implementation of such recommendations, dramatic increases in empiric ampicillin use have been observed with concurrent reductions in ceftriaxone prescribing for empiric CAP treatment. One site reported a reduction from 72% of patients receiving ceftriaxone to 21%, without any untoward impact on clinical outcomes.

In the face of many unique challenges and barriers, the management of pediatric infectious diseases continues to evolve and improve. Opportunities for research, discussion and advocacy must be taken for further advancement of this important field.

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For more information:
Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at lmolloy@dmc.org.

Disclosure: Molloy reports no relevant financial disclosures.