Worldwide, clinicians are seeing an increase in infections from antibiotic-resistant bacteria. According to the 2013 Centers for Disease Control and Prevention Threat Report, more than 2 million people in the United States are infected with one of these antibiotic-resistant bacteria, with 23,000 of those dying from the infection annually.1 This increase in resistance is driven by a number of factors including overuse of antibiotics in the clinical setting and in the food supply where antibiotic use in animal agriculture is thought to significantly increase our exposure to resistant organisms.2,3
In pediatrics, this trend of increasing antibiotic-resistant bacteria is especially worrisome. Pediatric caregivers are now seeing this problem in all settings, including the neonatal intensive care unit, the emergency department, and the outpatient clinic. A recent pediatric cohort study showed a greater than 700% increase of multidrug resistant (MDR) infections in children admitted to hospitals between 2007 and 2015.4 These MDR organisms cause infections of all types, such as urinary tract infections, blood stream infections, pneumonias, and meningitis. Furthermore, children infected with MDR organisms have increased morbidity and mortality compared to those with more susceptible organisms.5
Although this landscape appears bleak on many levels, there are some surprisingly good trends in pediatrics. Since the introduction of conjugated pneumococcal vaccines, the incidence of penicillin-resistant Streptococcus pneumoniae has decreased. In addition, methicillin-resistant Staphylococcus aureus (MRSA) infections have also decreased in the US. Although poorly understood, this decline in both adult and pediatric MRSA infections is a significant departure from the 2000s, where nearly one-half of the reported clinical S. aureus isolates in both inpatient and outpatient settings were MRSA.6
MDR Gram-negative bacteria are rapidly emerging as the most significant threat. Organisms producing extended spectrum beta-lactamases (ESBL) are resistant to commonly used penicillins and cephalosporins.7 Carbapenem use has increased in response, but in turn has been associated with a subsequent increase in carbapenem-resistant bacteria, including carbapenem-resistant Enterobacteriaceae (CRE). Reports describing increasing antibiotic resistance in pseudomonas, enterobacteriaceae, and other Gram-negative organisms infecting children in particular highlight the importance of addressing this problem. Nearly completely resistant Mycobacterium tuberculosis and Neisseria gonorrhoeae have now been identified and could potentially affect the at-risk pediatric population as well.8,9
Recognizing the problem of increasing antibiotic resistance, in 2014, President Barack Obama signed an executive order calling for a more concerted effort to combat antibiotic-resistant bacterial infections.10 Global calls to action further include coordinated efforts over time to reduce resistance on a much larger scale.11 In the short term, the diminishing armamentarium of antibiotics is even smaller for those treating children. Even though little effort is placed in the testing and approving of novel antibiotics, there are still some studies looking at new antibiotics and diagnostics. Through this article, we hope to share some strategies for pediatric caregivers concerned about antibiotic-resistant bacterial infections.
Novel Antibiotics for Resistant Gram-Positive Bacteria
Some of the most promising work in novel antibiotics has been seen in agents active against Gram-positive organisms. The spread of MRSA sparked significant efforts to treat MDR Gram-positive bacterial infections.12
Ceftaroline is a cephalosporin approved by the US Food and Drug Administration (FDA) in 2016 for use in children older than age 2 months with skin and soft tissue infections and community-acquired pneumonia. It is active against Gram-positive organisms including MRSA, resistant S. pneumoniae and beta-lactamase producing Haemophilus influenzae. It also has some Gram-negative activity against non-ESBL Escherichia coli and Klebsiella pneumoniae. Initially studied in adults and approved by the FDA in 2010, ceftaroline was shown to have similar clinical efficacy in skin and soft tissue infections caused by MRSA when compared to combination vancomycin and aztreonam therapy.13 After this, the first study of its use in pediatrics showed a higher cure rate in S. aureus infections (including MRSA) then either vancomycin or cefazolin.14 Additionally, in a more recent study looking at the activity of ceftaroline on pediatric isolates in vitro, ceftaroline was found to be efficacious against S. aureus (including MRSA) as well as penicillin- and ceftriaxone-resistant S. pneumoniae.15 There are numerous ongoing studies further evaluating the use of ceftaroline in the pediatric population.
In the last few years, the FDA approved two novel lipoglycopeptide antibiotics (same class as vancomycin). Dalbavancin is approved to treat acute bacterial skin and soft tissue infections in adults. With a long half-life, it is given intravenously once weekly, typically for a two-dose course. Information about pediatric dosing is now published, although not well studied.16 Telavancin is approved to treat both skin and soft tissue infections as well as hospital-acquired and ventilator-associated pneumonia due to S. aureus (including MRSA) in adults. Again, although well studied in adults, pediatric studies are yet to be published.12
Tidezolid is a novel oxazolidinone antibiotic (same class as linezolid) that is FDA approved for adult use in skin and soft tissue infections caused by Gram-positive organisms including MRSA. Both oral and parenteral forms have been shown to be non-inferior to linezolid in adults.17 Pediatric studies suggest safety, but clinical trials have not been published yet in children.
Novel Antibiotics for Resistant Gram-Negative Bacteria
Children with limited antibiotic options are often the ones who are at highest risk for poor outcomes from Gram-negative bacterial infections. There are two new beta-lactam/beta-lactamase inhibitor combinations targeting resistant Gram-negative organisms that may prove to be good options for treating MDR Gram-negative bacterial infections in children.
Approved in 2014 by the FDA for the treatment of complicated intra-abdominal and urinary tract infections in adults, ceftolozane/tazobactam is a beta-lactam/beta-lactamase inhibitor combination drug with activity against ESBL-producing bacteria as well as MDR Pseudomonas aeruginosa.18 Although ceftolozane/tazobactam is currently used only in adults, studies suggest potential utility for the treatment of resistant bacteria in pediatrics. In fact, one study of resistant Pseudomonas isolates from pediatric cystic fibrosis patients showed ceftolozane/tazobactam to be more active in vitro than meropenem, ceftazidime, and piperacillin/tazobactam.19 Another case report describes the successful use of ceftolozane/tazobactam in the treatment of a pediatric patient with leukemia with recurrent MDR Pseudomonas bacteremia.20
Ceftazidime/avibactam is another beta-lactam/beta-lactamase inhibitor antibiotic approved by the FDA in 2015 for the same indications as ceftolozane/tazobactam in adults. Avibactam is a beta-lactamase inhibitor that has a broader spectrum of activity than others of its class. It is active against ESBL-producing organisms, CREs, carbapenemase producers, and meropenem nonsusceptible Pseudomonas. To date, there are few published reports on the clinical use of ceftazidime/avibactam in pediatrics. However, a phase 1 study on a single dose of ceftazidime/avibactam in pediatric patients did demonstrate pharmacokinetics and safety in children similar to adults.21
Further studies in pediatrics are ongoing for both new beta-lactam/beta-lactamase inhibitor antibiotics. Other combination drugs targeting antibiotic-resistant Gram-negative bacteria are in development and in early clinical trials for adults.
A Return to Older Antibiotics
With the current dearth of novel antimicrobials available to pediatric practitioners, some older antibiotics previously set aside for a variety of reasons are now making a return. Many of them are rapidly becoming the only option in treating the more challenging MDR infections.
Colistin is a polymyxin antibiotic used in the treatment of infections with resistant Gram-negative organisms. It can be delivered parenterally or by inhalation. Despite being around for decades, it is still not commonly prescribed even among pediatric infectious disease specialists. Currently, pediatric use of colistin in the US is primarily in the population with cystic fibrosis for exacerbations and pneumonias, and when MDR Pseudomonas, Acinetobacter, or CRE is isolated.22 Unfortunately, there are no clear guidelines on pediatric dosing of colistin.
Fosfomycin is an antibiotic currently FDA approved for use as a single oral dose in adults with uncomplicated urinary tract infections caused by E. coli and E. faecalis. Fosfomycin's spectrum of activity is broad and includes CRE, MRSA, vancomycin-resistant Enterococcus as well as ESBL Gram-negative organisms. Unfortunately, there are minimal data about the use of fosfomycin in pediatric populations. Regardless, it is more commonly used in Europe and Asia, where it is approved for use in patients age 12 years and older. A parenteral formulation that is not readily available in the US has been used for the treatment of osteomyelitis, necrotizing pneumonia, brain abscesses, and complicated urinary tract infections due to resistant organisms.
New Methods for Antibiotic Discovery
Novel techniques for discovering antibiotics are being developed in response to global concerns about resistance. Regulatory bodies have been encouraged to speed up the approval processes required to get novel antibiotics to market.11 Researchers have now used improved methods to culture previously uncultivable bacteria from soil to identify teixobactin, representing a new class of antibiotics targeting bacterial cell wall lipids.23 This is the first novel class of antibiotics identified in decades. Resistance to teixobactin has not been identified. Clinical studies are ongoing. Previously identified small molecules/peptides are also now being screened and modified by many groups to look for activity against resistant bacteria.
Nonpharmacological Strategies against Antibiotic-Resistant Bacteria
Nonpharmacologic strategies to battle antibiotic-resistant bacteria remain fundamental. By optimizing therapy based on guidelines and local understanding of common pathogens, pediatric antimicrobial stewardship (AS) programs have significantly decreased not only unnecessary antibiotic use but also the development of resistant organisms.24,25 AS has become a cornerstone for hospitals working to prevent resistant bacterial infections, and guidelines for how to implement programs are available.25–27 Proposed shorter courses of antibiotics for common pediatric infections may also further assist in limiting antibiotic exposure, thus reducing the risk of developing resistant bacteria.27 Although pediatric infection prevention (IP) is poorly studied, standard precautions, hand hygiene, and cleaning and isolation protocols all remain key factors in preventing the further spread of resistant organisms within a health care environment.28 Further, infectious disease specialist involvement has been associated with decreased mortality and improved patient outcomes in treating infections due to resistant bacteria.29
Laboratory Detection of Antibiotic Resistance
Another important aspect in the battle against resistant bacteria is the development and implementation of new and improved laboratory detection. Panels using multiplex polymerase chain reactions to identify organisms and detect resistance genes or provide actual susceptibility test results within hours of a blood culture flagging positive are now available.30,31 This allows clinicians to tailor their antibiotic therapy more quickly. It is important to keep in mind that susceptibility testing for many of the newly FDA-approved antibiotics are not commercially available yet for clinical laboratories to implement but are in development.
Collaborative Approach to Combat Antibiotic-Resistant Bacteria
Pediatric clinicians have a unique role in the judicious use of antimicrobials, for we care for patients over a broad age range, from the neonatal period into adolescence and early adulthood. Understanding the changing dynamics between bacterial resistance and novel antibiotics helps us to better care for children now and in the future. We encourage you all to continue to work closely with your colleagues, infectious disease specialists, pharmacy, microbiology laboratory, AS program, and IP team on efforts to treat and reduce infections caused by antibiotic-resistant organisms. Ongoing pharmaceutical studies in children and broader global campaigns to limit antibiotic use remain vital in this fight. Only through a collaborative effort will the challenges posed by resistant bacteria be adequately addressed.
- Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States. https://www.cdc.gov/drugresistance/threat-report-2013/index.html. Accessed August 7, 2018.
- Paulson JA, Zaoutis TE. Nontherapeutic use of antimicrobial agents in animal agriculture: implications for pediatrics. Pediatrics. 2015;136(6):e1670–e1677. doi:. doi:10.1542/peds.2015-3630 [CrossRef]
- Gerber JS, Newland JG, Coffin SE, et al. Variability in antibiotic use at children's hospitals. Pediatrics. 2010;126(6):1067–1073. doi:10.1542/peds.2010-1275 [CrossRef]
- Meropol SB, Haupt AA, Debanne SM. Incidence and outcomes of infections caused by multidrug-resistant Enterobacteriaceae in children, 2007–2015. J Pediatric Infect Dis Soc. 2018;7(1):36–45. doi:. doi:10.1093/jpids/piw093 [CrossRef]
- Meropol SB, Haupt AA, Debanne SM. Incidence and outcomes of infections caused by multidrug-resistant enterobacteriaceae in children, 2007–2015. J Pediatr Infect Dis Soc. 2018;7(1):36–45. doi:. doi:10.1093/jpids/piw093 [CrossRef]
- Klein EY, Sun L, Smith DL, Laxminarayan R. The changing epidemiology of methicillin-resistant Staphylococcus aureus in the United States: a national observational study. Am J Epidemiol. 2013;177(7):666–674. doi:. doi:10.1093/aje/kws273 [CrossRef]
- Lukac PJ, Bonomo RA, Logan LK. Extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: old foe, emerging threat. Clin Infect Dis. 2015;60(9):1389–1397. doi:10.1093/cid/civ020 [CrossRef].
- Dheda K, Gumbo T, Maartens G, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis [published online ahead of print March 15, 2017]. Lancet Respir Med. doi:10.1016/S2213-2600(17)30079-6 [CrossRef].
- Papp JR, Abrams AJ, Nash E, et al. Azithromycin resistance and decreased ceftriaxone susceptibility in Neisseria gonorrhoeae, Hawaii, USA. Emerg Infect Dis. 2017;23(5):830–832. doi:. doi:10.3201/eid2305.170088 [CrossRef]
- The White House. President Barack Obama. Executive Order -- antibiotic-resistant bacteria. https://obamawhitehouse.archives.gov/the-press-office/2014/09/18/executive-order-combating-antibiotic-resistant-bacteria. Accessed August 22, 2018.
- World Health Organization. Global action plan on antimicrobial resistance. http://www.wpro.who.int/entity/drug_resistance/resources/global_action_plan_eng.pdf. Accessed August 7, 2018.
- Gostelow M, Gonzalez D, Smith PB, Cohen-Wolkowiez M. Pharmacokinetics and safety of recently approved drugs used to treat methicillin-resistant Staphylococcus aureus infections in infants, children and adults. Exp Rev Clin Pharmacol. 2014;7(3):327–340. doi:. doi:10.1586/17512433.2014.909281 [CrossRef]
- Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis. 2010;51(6):641–650. doi:10.1086/655827 [CrossRef]
- Korczowski B, Antadze T, Giorgobiani M, et al. A multicenter, randomized, observer-blinded, active-controlled study to evaluate the safety and efficacy of ceftaroline versus comparator in pediatric patients with acute bacterial skin and skin structure infection. Pediatr Infect Dis J. 2016;35(8):e239–e247. doi:. doi:10.1097/INF.0000000000001191 [CrossRef]
- Pfaller MA, Mendes RE, Castanheira M, Flamm RK, Jones RN, Sader HS. Ceftaroline activity tested against bacterial isolates causing community-acquired respiratory tract infections and skin and skin structure infections in pediatric patients from United States hospitals: 2012–2014. Pediatr Infect Dis J. 2017;36(5):486–491. doi:. doi:10.1097/INF.0000000000001477 [CrossRef]
- Gonzalez D, Bradley JS, Blumer J, et al. Dalbavancin pharmacokinetics and safety in children 3 months to 11 years of age. Pediatr Infect Dis J. 2017;36(7):645–653. doi:. doi:10.1097/INF.0000000000001538 [CrossRef]
- Sandison T, De Anda C, Fang E, Das AF, Prokocimer P. Clinical response of tedizolid versus linezolid in acute bacterial skin and skin structure infections by severity measure using a pooled analysis from two phase 3 double-blind trials. Antimicrob Agents Chemother. 2017;61(5):e02687. doi:. doi:10.1128/AAC.02687-16 [CrossRef]
- Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2014;74(1):31–51. doi:. doi:10.1007/s40265-013-0168-2 [CrossRef]
- Kuti JL, Pettit RS, Neu N, et al. Microbiological activity of ceftolozane/tazobactam, ceftazidime, meropenem, and piperacillin/tazobactam against Pseudomonas aeruginosa isolated from children with cystic fibrosis. Diagn Microbiol Infect Dis. 2015;83(1):53–55. doi:. doi:10.1016/j.diagmicrobio.2015.04.012 [CrossRef]
- Aitken SL, Kontoyiannis DP, DePombo AM, et al. Use of ceftolozane/tazobactam in the treatment of multidrug-resistant pseudomonas aeruginosa bloodstream infection in a pediatric leukemia patient. Pediatr Infect Dis J. 2016;35(9):1040–1042. doi:. doi:10.1097/INF.0000000000001228 [CrossRef]
- Bradley JS, Armstrong J, Arrieta A, et al. Phase I study assessing the pharmacokinetic profile, safety, and tolerability of a single dose of ceftazidime-avibactam in hospitalized pediatric patients. Antimicrob Agents Chemother.2016;60(10):6252–6259. doi:. doi:10.1128/AAC.00862-16 [CrossRef]
- Tamma PD, Newland JG, Pannaraj PS, et al. The use of intravenous colistin among children in the United States: results from a multicenter, case series. Pediatr Infect Dis J. 2013;32(1):17–22. doi:. doi:10.1097/INF.0b013e3182703790 [CrossRef]
- Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015;517(7535):455–459. doi:. doi:10.1038/nature14098 [CrossRef]
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- Society for Healthcare Epidemiology of America; Infectious Diseases Society of America; Pediatric Infectious Diseases Society. Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol.2012;33(4):322–327. doi:. doi:10.1086/665010 [CrossRef]
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